Embryology - User contributions [en-gb]

2018 Group Project 1

2018-10-16T13:04:50Z

Z5113627: /* Related Anatomy */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===

----

The neural crest of an embryo migrates and differentiates to form various components of the body. This transient population of pluripotent stem-cells give rise to many complex and different structures across the adult by chemical signalling. One of these tissues is the medulla of the adrenal gland which is involved in the production of epinephrine and norepinephrine. This project will comprehensively outline the history of neural crest research, the embryonic developmental time course, tissue and organ structure, molecular mechanisms, abnormalities, animal models and current research.

===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
[[File:NC Location.jpg|right|450px|thumb|The neural crest]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to {{#pmid:19179766|PMID19179766}} This was due to his work in creating one of the first microtomes, a device that enables thin slicing of tissue. This enabled him to see embryonic tissues at greater magnifications and resolutions and gave the neural crest the name, the ganglionic crest {{#pmid:26970616|PMID26970616}}. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

This period from the 1890s to the 1950s was a time of emerging research and experimentation, with various contributions of the neural crest being studied. This was done through a range of experiments involving removal of parts of the neural crest to examine the effects on development of birds and amphibians as well as transplantation of parts of neural crest to enable an understanding of patterns of cell migration {{#pmid:26970616|PMID26970616}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was done through new techniques involving marking the cells with radioactive substances such as 3H-thymidine {{#pmid:26970616|PMID26970616}}. This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb|465px]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

In the mid 1980s, the first studies bringing about some information on the destination of ventrally migrating neural crest cells were conducted using the antibody HNK-1, as it is known to detect antigens on neuroectodermal cells & label the migratory cells. Where previously it was thought that trunk neural crest cells migrated whilst avoiding the somites, these studies showed that the trunk neural crest cells migrated through the rostral half of each somite. How this worked was eventually understood as a result of chemotactic factors that attract and repel the cells to follow this migration {{#pmid:26970616|PMID26970616}}.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins {{#pmid:22230617|PMID22230617}}.
. Advances in technology will undeniably lead us to more answers on the subject and studies that include imaging, mathematical and molecular modelling will greatly enhance our growing understanding of how neural crest cells move {{#pmid:26970616|PMID26970616}}.

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Embryonic origins===
----
[[File:Trunk_NCC_migration.jpg|left|450px|thumb|Trunk NCC migration]]
The adrenal gland is made up of the adrenal cortex and adrenal medulla, which both have different embryonic origins. The adrenal medulla arises from the neural crest tissue, found near the level of the coeliac plexus & sympathetic ganglion at somites 18-24 {{#pmid:16124976|PMID16124976}}. Specifically, this neural crest tissue comes from the trunk neural crest cells (see above figure to determine the approximate location in an embryo) <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
The trunk neural crest coordinates the development of the endocrine system, secretory cells, the peripheral nervous system and, to some degree, skeletal development, as well as innervation of the intestine {{#pmid: 28287247|PMID 28287247}}. The trunk neural cells arise caudally, undergo an epithelial to mesenchymal transition and follow three migratory pathways {{#pmid:20399766|PMID20399766}}.
[[File:Differentiation_of_NCC.jpg|left|580px|thumb|Differentiation of chromaffin cells]]
- A dorsolateral pathway (between ectoderm and somites), these become melanocytes, travel up to the point of the dermis and become a major part of the hair follicles and skin <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
- A ventrolateral pathway (through the somites)
- A ventromedial pathway (between neural tube and posterior schlerotome){{#pmid:20399766|PMID20399766}}.

Migration of neural crest cells from the sympathetic ganglion is what leads to the development of the adrenal medulla. In week 8 of development, immature cells called neuroblasts migrate through to the inner portion of the medulla, where they become the adrenal medulla {{#pmid:19683477|PMID19683477}}. Chromaffin cells are neuroendocrine cells and are found in the sympathetic ganglia and make up the majority of the adrenal medulla{{#pmid:19683477|PMID19683477}}. They synthesise and release a range of hormones in the body and arise from the temporary neural crest. The term chromaffin was inspired by the staining capacity of these cells when they came into contact with chrome salts. They make, store, export and use catecholamines, responsible for making noradrenaline and originate at the caudal region of somites 18-24 of the neural crest, also known as the adrenomedullary region {{#pmid:19683477|PMID19683477}}.

For cells to leave the neural crest and begin their migration, certain conditions need to be met, that is, the cells need to be loosely connected, their tight junctions becoming relaxed, initiated by "Slug protein" and a loss of N-Cadherin which also leads to the loosening of these junctions. The surrounding matrix as well as chemotactic and stem cell factors of the neural tube are then what dictates how the neural crest cells move, some proteins stopping their migration to that area and others encouraging the movement <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. After splitting apart, the first neural crest cells move ventrally and pass into the spaces between the somites and then, through the anterior portions of each segment until they arrive at the para-aortic sites, where they become the cells of the sympathetic ganglia and the adrenal medulla {{#pmid:19683477|PMID19683477}}. BMP-4 (bone morphogenetic protein 4) then acts on these neural crest cells, preventing them from becoming cells that have a neural function and causing them to become chromaffin cells at the adrenal medulla. Glucocorticoids then play a role in maintenance of chromaffin cells in postnatal life, this was only found recently, as previously it was thought that glucocorticoids were responsible entirely for the differentiation of neural crest cells into chromaffin, or adrenomedullary cells {{#pmid:23220335|PMID23220335}}.

===Anatomy and Functions===

----

====Anatomy and Histology====

The adrenal medulla makes up the inner section of the adrenal glands, and is surrounded by the cortex, and a connective tissue capsule. It lies in the centre of the gland and it rarely measures no more than 2mm in thickness {{#pmid:21107679|PMID21107679}}. The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The adrenal medulla contains secretory cells called chromaffin cells due to the agents they produce when oxidised, such as chromate {{#pmid:11215683|PMID11215683}}. These cells secrete epinephrine, norepinephrine, chromogranin and neuropeptides in response to various substances such as acetylcholine <ref name="PMID11215683"/>. [[File:ADRENAL MEDULLA .jpg|600px|thumb|right|Adrenal Medulla Histology]]

There are many types of highly differentiated cells in the adult adrenal medulla:
- Epinephrine cells (90% of all chromaffin cells) {{#pmid:24715564|PMID24715564}}
- Norepinephrine cells (10% of all chromaffin cells) <ref name="PMID24715564"/>
- Small granule-containing cells (SGCs) <ref name="PMID11215683"/>

These cells also synthesise, store and secrete catecholamines through controlled and regulated pathways <ref name="PMID24715564"/>, such as various peptides like substance P and neurotensin.These cells have unique neuroendocrine characteristics as a result of their neural-crest origin. They receive preganglionic innervation by thoracic splanchnic nerves, and could almost be considered a specialised sympathetic ganglion. With postganglgionic bodies, cells of the medulla are densely clustered around their vasculature for the secretion of hormones into the bloodstream to moderate the concentration of epinephrine and norepinephrine. The adrenal medulla also contains presynaptic sympathetic ganglion cells <ref name="PMID11215683"/>. The small granule-containing cells are usually found in clusters whereas, the ganglion cells are found either individually or in clusters, usually dispersed among the chromaffin cells or among the nerve fibres {{#pmid:18021328|PMID18021328}}. During embryonic development (around weeks 9-12), in contrast to the developing adrenal cortex, the medulla does not show evidence of an organised structure other than a small cluster of cells scattered throughout its cortex {{#pmid:30247985|PMID30247985}}.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of epinephrine and norepinephrine in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands and its medulla are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way with a rich surface area.

The adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus. {{#pmid:11215683|PMID11215683}}

[[File:Dd.jpg|400px|thumb|right|Adult Adrenal Glands in situ]]
----

====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses. {{#pmid:19396395|PMID19396395}}

'''Adult Function'''

While the adrenal cortex releases glucocorticoids in response to long term stress, the adrenal medulla releases its hormones in response to short-term, acute stress. The adrenal medulla contains the neuroendocrine chromaffin cells which are responsible for secreting adrenaline and noradrenaline. The function of these hormones is primarily to maintain the body’s homeostasis, especially of the internal organs, and to properly activate the autonomic stress response, more commonly known as the ‘fight or flight’ response {{#pmid:30237243|PMID30237243}}. Thus the function of the medulla includes signalling the liver and skeletal muscles to convert glycogen into glucose for increased energy. This results in increased blood glucose levels. These hormones also increase the heart rate, pulse and blood pressure in preparation for the fight or flight response. In addition to this, these hormones dilate the lung airways and prompt vasodilation to further increase oxygenation of important organs such as the lung, brain and heart. Vasoconstriction of blood vessels is also prompted to other less essential organs such as the bladder and the digestive system.

Other effects also include pupil dilation, dry mouth and a loss in peripheral vision <ref name="PMID18021328"/>. Paramount to the correct response of chromaffin cells is the synaptic connection of the preganglionic cells which originate from the central nervous system and project axons into the adrenal medulla. While this is a very important relationship, the mechanisms of this remains unknown <ref name="PMID30237243"/>. In addition to the release of catecholamines, cells in the medulla also release peptides through the process of exocytosis from chromaffin granules, to help regulate blood pressure and regulation throughout the body. These peptides also regulate the release of adrenaline and noradrenaline, blood vessel contraction and the immune response <ref name="PMID18021328"/>.

'''Embryonic function'''

The current knowledge about the development of the adrenal gland is limited, with nearly all models being from animals, and very limited functional data available from human fetal adrenals <ref name="PMID30247985"/>. Thus for these reasons, there is scarce information available on the embryonic adrenal medullary functions. Nevertheless, there is accumulating evidence that the catecholamines in the fetal adrenal medulla plays an important role in the time of delivery by controlling thermogenesis and heart regulation {{#pmid:6998630|PMID6998630}}.

The hormones released by the medulla during birth also play a key role for the newborn’s adaptation to extrauterine life. Despite the immaturity of the adrenal medulla at birth, it is known that respiratory, metabolic and cardiovascular changes during delivery are dependent on the adrenomedullary hormones {{#pmid:3280659|PMID3280659}}. Experimental data from human and animal fetal research shows that the fetal sympathoadrenal system, consisting of the adrenal medulla, sympathetic neurons and chromaffin tissue work together to maintain fetal homeostasis {{#pmid:6346884|PMID6346884}}. The adrenal medulla thus appears to provide vital physiological functions for fetal and neonatal survival, especially during birth.

----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

The 'story' of the Adrenal Medulla's neural crest tissue begins at the process of neurulation, the formation of the neural tube from the folding neural plate, which is comprised of developing ectoderm which is opposite to the primitive streak. It is here that several key chemical players are at work. The classic interpretation of Sonic Hedgehog (Shh) and Wnt signalling pathways as the only mediators here, has been shown to be incorrect. Research has uncovered other signallers such as:

*Bone-Morphogenic-Protein-4 (BMP4) for the regional expression of nervous system distinctions in the growing neural plate. This maintains two important embryonic trancription factors known as Paired-Box (PAX) Genes 3 and 7 which can allow for expression of neural crest markers HNK-1, SRY-Box (SOX) 8, 9 and 10 as the neural tube closes and the neural crest delaminates from the folding. {{#pmid:16688176|PMID16688176}}

*Slug via Wnt signalling, this allows for the loosening of gap junctions in the extracellular matrix surrounding the newly-formed neural tube and trunk of the embryo. This extracellular matrix has chemo-attractant molecules

[[File:Catecholamine_Synthesis.jpg|400px|thumb|right|Biochemical Cascade of Catecholamine Synthesis]]

The importance of Somitogenesis and Neural Crest come to a head when neural crest cells must migrate anteriorly past somites 18 to 24, utilising chemoattraction from cells of the extracellular matrix between the neural tube and Adrenal Cortex's primordial mesoderm

Members of the SOX gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands. {{#pmid:18272785|PMID18272785}}

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well. {{#pmid:19396395|PMID19396395}}

===Abnormalities/abnormal development===
----

Abnormalities of the Adrenal Medulla are much less common than its mesoderm-derived shell of the Adrenal Gland. Three of the most notorious abnormalities of the Adrenal Medulla include:

* Pheochromocytomas
* Ganglioneuromas
* Neuroblastomas

Pheochromocytomas (PCCs) are variable neoplasias of the adrenal medulla's chromaffin cells. There are many classifications of PCCs, with autosomal-dominant germ-line mutations and heredities being one of the main causes. Familial pheochromocytoma-paraganglioma (PGL) syndromes exist, with PGL1 having mutations of the SDHD gene, PGL3 being mutated of the SDHC gene and PGL4 having mutation of the SDHB gene. These phenotypically present as extra-adrenal chromaffin bodies, malformation of the adrenal glands themselves, absence of chromaffin bodies and fluctuations in circulating catecholamines. {{#pmid:18021328|PMID18021328}}

Ganglioneuromas (GNs) are classically-benign growths that are very rare and arise from neural crest tissue. They are not circumscribed to the adrenal medulla, but also are found in the sympathetic chain and trunk ganglia. As a result of their scarcity, not much is known about them other than a few aberrant genes and generic clinical presentations. ERBB3, the receptor tyrosine kinas is understood to be important in the development of GNs, as well as an extremely high prevalence of up-regulated GATA3. A key thing to note is also the '''lack''' of N-MYC expression in GNs, which is quite prominent in neuroblastomas and other neoplasias. {{#pmid:29085827|PMID29085827}} {{#pmid:23715162|PMID23715162}}

Neuroblastomas (NBs) are a more aggressive form of cancer, derived from neuroblasts - the precursor cells to neurons. A rather common pediatric cancer, they are often in children who are in risk factor groups such as those with aforementioned familial cancer syndromes, neurofibromatosis-1. These tumours often present with extremely variable catecholamine concentrations, which has implications for blood pressure, heart contractility and much more. Urinary excretion of norepinephrine, homovanillic acid (HVA) and vanilmandelic acid (VMA) can be used to help diagnose a suspected lesion of the adrenal gland, as these chemicals are associated with altered chemical cascades that are suspicious of neuroblastic change. {{#pmid:16372223|PMID16372223}}

Apart from these abnormalities, there are other pathologies that may be connected to the adrenal medulla. One such example is a pathology of the Organ of Zuckerkandl. Also known as the para-aortic body, the Organ of Zuckerkandl is a primarily-gestational organ comprised of chromaffin cells and serves a similar purpose to the adrenal medulla in neonatal life.

===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

====Chromaffin cells====
There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells{{#pmid:19377845|PMID19377845}}. The neural crest cells give rise to chromaffin cells of the adrenal medulla.

=====Rat Models=====
[[File:Adrenal gland.png|300px|thumb|right|3D images showing TH - positive cells accumulating at the cranial and Caudal ends of the adrenal gland.]]
Previous research has reported that nueral crest cells differentiate into chromaffin cells around 19 days of gestation before forming the adrenal medulla{{#pmid:28684471|PMID2868441}}. Past research had also suggested that neural crest derived adrenal gland cells migrate using the sympathetic ganglia to the adrenal gland or preaortic ganglion, following different pathways, to reach their specific destination. However the results have shown that the pathways used to reach its destinations overlapped. This would suggest that there is a possibility of the cells using the same pathway to move from the beginning production to the destination that is the adrenal medulla (for chromaffin cells) and the preaortic ganglion (other cells involved in the sympathetic system).

One particular study done by M.Yamato in 2004, along with his fellow scientists attempted to study the migration of neural crest cells in Wistar rats. In order to observe the formation adrenal medulla from the neural crest cells during the embryonic period, Yamato used anti - tyrosine hydroxylase (TH) antiserum injected into the rat embryos between 13-17 days of gestation. The anti - TH antiserum stain allows the scientists to visualize the neural crest cells under a light microscope. Later three dimensional images were created. From the images observed between 13 to 15 days of gestation, the TH - positive cells can be seen to move from the dorsal to the adrenal primordium{{#pmid:15240937|PMID15240937}}. After 16 days it was observed that a capsule had formed in some parts and TH - positive cells had penetrated the adrenal gland{{#pmid:15240937|PMID15240937}}. At seventeen days, TH - positive cells can be seen collecting at the medial part of the adrenal gland. The reconstructed images also shows that at the later stages during the 16-17 days of gestation, the accumulation of TH - positive cells grow and in combination with cell division leads to the formation of the adrenal medulla.

=====Chicken models=====
Chicken and rat models are often the most commonly used models when dealing with neural crest cells. A particle review article, collates multiple researchers results and presents evidence to discuss previous information suggesting that sympathetic neurons and chromaffin cells do not share a common progenitor{{#pmid:3693940|PMID3693940}}. The relevant study involved the use of cell cultures, Sympathoadrneal (SA) progenitor cells from embryonic(from chick embryos) and eary developmental stages were able to be procured. From these cultures it was easy to identify that glucocorticoids were crucial in the differentiation of SA cells into their derivatives, sympathetic neurons and chromaffin cells.

[[File:Expression of BMP protein 4 .jpg|300px|thumb|right|Shows the movement of the chromaffin progenitors moving from each stage of development. sg: sympathetic ganglia ac:adrenal cortical region ag: adrenal gland da: dorsal aortic region]]

Another study conducted deals with the role of the bone morphogenetic protein(BMP-4) and its importance in the development of the adrenal medullary cells, chromaffin cells{{#pmid:18945349|PMID18945349}}. Previous research had shown that BMP - 4 a growth factor is plays an important role in the regulation of chromaffin cell production{{#pmid:10679774|PMID10679774}}. The researchers incubated chick embryos for 3 - 9 embryonic days and dissected them to be used for tissue cultures. Embryonic day 8 chick embryos had BMP - 4 overexpressing cells implanted in the sympathetic ganglia area, as well as other neurons which contained chromaffin like cells. What was observed was an increase in size and numbers of 'chromaffin' granules{{#pmid:18945349|PMID18945349}}. As a result it was concluded that although BMP - 4 promotes certain chromaffin traits, it does not have the capability to convert sympathetic neurons into a chromaffin type cell.

===Current research (labs)===
----

==== Generation of Adrenal Chromaffin-like Cells from Human Pluripotent Stem Cells====

As explained above the adrenal medulla plays an important part in the autonomic system of an adult human. The chromaffin cells, in particular, are important neural crest derived cell that is closely related to the adrenal medulla. Previous findings have focused specifically on the mechanisms controlling the neural crest cell migration and how these cells go on to form the different derivatives in their particular destinations in the embryo. For example, as previously explained studies have shown that chromaffin cells have been observed to move to the adrenal gland to form the medulla of the adrenal gland. This report goes through a recent study that involves the adrenal medullary cells, in particular chromaffin cells, and their potential to be used to model certain pathological diseases related to these cells. This is part of a study that also involves neural crest cells and their ability to differentiate into multiple different types of cells<ref>Lumb, R., & Schwarz, Q. (2015). Sympathoadrenal neural crest cells: The known, unknown and forgotten?. Development, Growth & Differentiation, 57(2), 146-157. doi: 10.1111/dgd.12189</ref>. Neural crest cells and SAPs from human embryonic cells and induced pluripotent stem cells were generated to be used in the experiment. By exposing the pluripotent stem cells to BMP4 in vitro, results showed that these cells would 'upregulate' the chromaffin cell - specific marker PMNT (an enzyme that synthesizes adrenaline). Furthermore when the cells from human embryos were implanted into avian embryos, there was a visible potential for the human cells to differentiate into cells that expressed the chromaffin cell markers{{#pmid:5768882|PMID5768882}}.

Link to article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/

====Multipotent Peripheral Glial Cells Generate Neuroendocrine Cells of the Adrenal Medulla====

Similar to the first study, this one also focuses on the chromaffin cells and their relationship to the adrenal medulla. Chromaffin cells often represent the main endocrine component that is believed to differentiate from neural crest cells{{#pmid:28684471|PMID28684471}}. The study focuses specifically on the idea that previous research has suggested that nerve - associated schwann cell precursor is a progenitor of chromaffin cells. What the findings suggested was that peripheral nerves provided migration routes for the progenitors. This is backed up by the results, a high concentration of chromaffin cells can be found being derived from the nerve, as nerve ablated mice in the experiment showed a large difference of 78% less cells compared to the control. Other than this, the study also brought to light the proliferative potential of the cells from nerves, with different other cell types being discovered as well (including cells such as parasympathetic{{#pmid:24925912|PMID24925912}} and melanocytes {{#pmid:19837037 |PMID19837037}}). The findings would provide useful information into further understanding the adrenal gland and its embryonic origins (as there is still much to learn regarding the formation of the adrenal medulla) but also pathological diseases such as neuroblastoma and pheochromatocytoma which are most common in the adrenal glandular region {{#pmid:23106811|PMID23106811}}.

Link to article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013038/

===Glossary===
----
*BMP4 - Bone Morphogenic Protein 4
*DOPA - Dihydroxyphenylalanine
*GATA3 - Transcription factor 3 for GATA gene
*GN - Ganglioneuroma
*GRN - Gene Regulatory Network
*HNK1 - Human Natural Killer 1
*HVA - Homovanillic Acid
*L-DOPA - L-3,4-dihydroxyphenylalanine
*NB - Neuroblastoma
*PAX - Paired Box
*PCC - Pheochromocytoma
*PGL - Pheochromocytoma Paraganglioma
*PNMT - phenylethanolamine-N-methyltransferase
*SGC - Small Granule Containing cells
*SOX - Sry Box
*TH - Tyrosine Hydroxylase
*VMA -Vanilmandelic Acid

===Reference list===

2018 Group Project 1

2018-10-16T11:48:54Z

Z5113627: /* Genes and Transcription Factors Involved with the Adrenal Medulla's Development */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===

----

The neural crest of an embryo migrates and differentiates to form various components of the body. This transient population of pluripotent stem-cells give rise to many complex and different structures across the adult by chemical signalling. One of these tissues is the medulla of the adrenal gland which is involved in the production of epinephrine and norepinephrine. This project will comprehensively outline the history of neural crest research, the embryonic developmental time course, tissue and organ structure, molecular mechanisms, abnormalities, animal models and current research.

===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
[[File:NC Location.jpg|right|450px|thumb|The neural crest]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to {{#pmid:19179766|PMID19179766}} This was due to his work in creating one of the first microtomes, a device that enables thin slicing of tissue. This enabled him to see embryonic tissues at greater magnifications and resolutions and gave the neural crest the name, the ganglionic crest {{#pmid:26970616|PMID26970616}}. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

This period from the 1890s to the 1950s was a time of emerging research and experimentation, with various contributions of the neural crest being studied. This was done through a range of experiments involving removal of parts of the neural crest to examine the effects on development of birds and amphibians as well as transplantation of parts of neural crest to enable an understanding of patterns of cell migration {{#pmid:26970616|PMID26970616}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was done through new techniques involving marking the cells with radioactive substances such as 3H-thymidine {{#pmid:26970616|PMID26970616}}. This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb|465px]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

In the mid 1980s, the first studies bringing about some information on the destination of ventrally migrating neural crest cells were conducted using the antibody HNK-1, as it is known to detect antigens on neuroectodermal cells & label the migratory cells. Where previously it was thought that trunk neural crest cells migrated whilst avoiding the somites, these studies showed that the trunk neural crest cells migrated through the rostral half of each somite. How this worked was eventually understood as a result of chemotactic factors that attract and repel the cells to follow this migration {{#pmid:26970616|PMID26970616}}.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins {{#pmid:22230617|PMID22230617}}.
. Advances in technology will undeniably lead us to more answers on the subject and studies that include imaging, mathematical and molecular modelling will greatly enhance our growing understanding of how neural crest cells move {{#pmid:26970616|PMID26970616}}.

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Embryonic origins===
----
[[File:Trunk_NCC_migration.jpg|left|450px|thumb|Trunk NCC migration]]
The adrenal gland is made up of the adrenal cortex and adrenal medulla, which both have different embryonic origins. The adrenal medulla arises from the neural crest tissue, found near the level of the coeliac plexus & sympathetic ganglion at somites 18-24 {{#pmid:16124976|PMID16124976}}. Specifically, this neural crest tissue comes from the trunk neural crest cells (see above figure to determine the approximate location in an embryo) <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
The trunk neural crest coordinates the development of the endocrine system, secretory cells, the peripheral nervous system and, to some degree, skeletal development, as well as innervation of the intestine {{#pmid: 28287247|PMID 28287247}}. The trunk neural cells arise caudally, undergo an epithelial to mesenchymal transition and follow three migratory pathways {{#pmid:20399766|PMID20399766}}.
[[File:Differentiation_of_NCC.jpg|left|580px|thumb|Differentiation of chromaffin cells]]
- A dorsolateral pathway (between ectoderm and somites), these become melanocytes, travel up to the point of the dermis and become a major part of the hair follicles and skin <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
- A ventrolateral pathway (through the somites)
- A ventromedial pathway (between neural tube and posterior schlerotome){{#pmid:20399766|PMID20399766}}.

Migration of neural crest cells from the sympathetic ganglion is what leads to the development of the adrenal medulla. In week 8 of development, immature cells called neuroblasts migrate through to the inner portion of the medulla, where they become the adrenal medulla {{#pmid:19683477|PMID19683477}}. Chromaffin cells are neuroendocrine cells and are found in the sympathetic ganglia and make up the majority of the adrenal medulla{{#pmid:19683477|PMID19683477}}. They synthesise and release a range of hormones in the body and arise from the temporary neural crest. The term chromaffin was inspired by the staining capacity of these cells when they came into contact with chrome salts. They make, store, export and use catecholamines, responsible for making noradrenaline and originate at the caudal region of somites 18-24 of the neural crest, also known as the adrenomedullary region {{#pmid:19683477|PMID19683477}}.

For cells to leave the neural crest and begin their migration, certain conditions need to be met, that is, the cells need to be loosely connected, their tight junctions becoming relaxed, initiated by "Slug protein" and a loss of N-Cadherin which also leads to the loosening of these junctions. The surrounding matrix as well as chemotactic and stem cell factors of the neural tube are then what dictates how the neural crest cells move, some proteins stopping their migration to that area and others encouraging the movement <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. After splitting apart, the first neural crest cells move ventrally and pass into the spaces between the somites and then, through the anterior portions of each segment until they arrive at the para-aortic sites, where they become the cells of the sympathetic ganglia and the adrenal medulla {{#pmid:19683477|PMID19683477}}. BMP-4 (bone morphogenetic protein 4) then acts on these neural crest cells, preventing them from becoming cells that have a neural function and causing them to become chromaffin cells at the adrenal medulla. Glucocorticoids then play a role in maintenance of chromaffin cells in postnatal life, this was only found recently, as previously it was thought that glucocorticoids were responsible entirely for the differentiation of neural crest cells into chromaffin, or adrenomedullary cells {{#pmid:23220335|PMID23220335}}.

===Anatomy and Functions===

----

====Anatomy and Histology====

The adrenal medulla makes up the inner section of the adrenal glands, and is surrounded by the cortex, and a connective tissue capsule. It lies in the centre of the gland and it rarely measures no more than 2mm in thickness {{#pmid:21107679|PMID21107679}}. The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The adrenal medulla contains secretory cells called chromaffin cells due to the agents they produce when oxidised, such as chromate {{#pmid:11215683|PMID11215683}}. These cells secrete epinephrine, norepinephrine, chromogranin and neuropeptides in response to various substances such as acetylcholine <ref name="PMID11215683"/>. [[File:ADRENAL MEDULLA .jpg|600px|thumb|right|Adrenal Medulla Histology]]

There are many types of highly differentiated cells in the adult adrenal medulla:
- Epinephrine cells (90% of all chromaffin cells) {{#pmid:24715564|PMID24715564}}
- Norepinephrine cells (10% of all chromaffin cells) <ref name="PMID24715564"/>
- Small granule-containing cells (SGCs) <ref name="PMID11215683"/>

These cells also synthesise, store and secrete catecholamines through controlled and regulated pathways <ref name="PMID24715564"/>, such as various peptides like substance P and neurotensin.These cells have unique neuroendocrine characteristics as a result of their neural-crest origin. They receive preganglionic innervation by thoracic splanchnic nerves, and could almost be considered a specialised sympathetic ganglion. With postganglgionic bodies, cells of the medulla are densely clustered around their vasculature for the secretion of hormones into the bloodstream to moderate the concentration of epinephrine and norepinephrine. The adrenal medulla also contains presynaptic sympathetic ganglion cells <ref name="PMID11215683"/>. The small granule-containing cells are usually found in clusters whereas, the ganglion cells are found either individually or in clusters, usually dispersed among the chromaffin cells or among the nerve fibres {{#pmid:18021328|PMID18021328}}. During embryonic development (around weeks 9-12), in contrast to the developing adrenal cortex, the medulla does not show evidence of an organised structure other than a small cluster of cells scattered throughout its cortex {{#pmid:30247985|PMID30247985}}.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus. {{#pmid:11215683|PMID11215683}}

[[File:Dd.jpg|400px|thumb|right|Adult Adrenal Glands in situ]]
----
====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses. {{#pmid:19396395|PMID19396395}}

'''Adult Function'''

While the adrenal cortex releases glucocorticoids in response to long term stress, the adrenal medulla releases its hormones in response to short-term, acute stress. The adrenal medulla contains the neuroendocrine chromaffin cells which are responsible for secreting adrenaline and noradrenaline. The function of these hormones is primarily to maintain the body’s homeostasis, especially of the internal organs, and to properly activate the autonomic stress response, more commonly known as the ‘fight or flight’ response {{#pmid:30237243|PMID30237243}}. Thus the function of the medulla includes signalling the liver and skeletal muscles to convert glycogen into glucose for increased energy. This results in increased blood glucose levels. These hormones also increase the heart rate, pulse and blood pressure in preparation for the fight or flight response. In addition to this, these hormones dilate the lung airways and prompt vasodilation to further increase oxygenation of important organs such as the lung, brain and heart. Vasoconstriction of blood vessels is also prompted to other less essential organs such as the bladder and the digestive system.

Other effects also include pupil dilation, dry mouth and a loss in peripheral vision <ref name="PMID18021328"/>. Paramount to the correct response of chromaffin cells is the synaptic connection of the preganglionic cells which originate from the central nervous system and project axons into the adrenal medulla. While this is a very important relationship, the mechanisms of this remains unknown <ref name="PMID30237243"/>. In addition to the release of catecholamines, cells in the medulla also release peptides through the process of exocytosis from chromaffin granules, to help regulate blood pressure and regulation throughout the body. These peptides also regulate the release of adrenaline and noradrenaline, blood vessel contraction and the immune response <ref name="PMID18021328"/>.

'''Embryonic function'''

The current knowledge about the development of the adrenal gland is limited, with nearly all models being from animals, and very limited functional data available from human fetal adrenals <ref name="PMID30247985"/>. Thus for these reasons, there is scarce information available on the embryonic adrenal medullary functions. Nevertheless, there is accumulating evidence that the catecholamines in the fetal adrenal medulla plays an important role in the time of delivery by controlling thermogenesis and heart regulation {{#pmid:6998630|PMID6998630}}.

The hormones released by the medulla during birth also play a key role for the newborn’s adaptation to extrauterine life. Despite the immaturity of the adrenal medulla at birth, it is known that respiratory, metabolic and cardiovascular changes during delivery are dependent on the adrenomedullary hormones {{#pmid:3280659|PMID3280659}}. Experimental data from human and animal fetal research shows that the fetal sympathoadrenal system, consisting of the adrenal medulla, sympathetic neurons and chromaffin tissue work together to maintain fetal homeostasis {{#pmid:6346884|PMID6346884}}. The adrenal medulla thus appears to provide vital physiological functions for fetal and neonatal survival, especially during birth.

----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

The 'story' of the Adrenal Medulla's neural crest tissue begins at the process of neurulation, the formation of the neural tube from the folding neural plate, which is comprised of developing ectoderm which is opposite to the primitive streak. It is here that several key chemical players are at work. The classic interpretation of Sonic Hedgehog (Shh) and Wnt signalling pathways as the only mediators here, has been shown to be incorrect. Research has uncovered other signallers such as:

*Bone-Morphogenic-Protein-4 (BMP4) for the regional expression of nervous system distinctions in the growing neural plate. This maintains two important embryonic trancription factors known as Paired-Box (PAX) Genes 3 and 7 which can allow for expression of neural crest markers HNK-1, SRY-Box (SOX) 8, 9 and 10 as the neural tube closes and the neural crest delaminates from the folding. {{#pmid:16688176|PMID16688176}}

*Slug via Wnt signalling, this allows for the loosening of gap junctions in the extracellular matrix surrounding the newly-formed neural tube and trunk of the embryo. This extracellular matrix has chemo-attractant molecules

[[File:Catecholamine_Synthesis.jpg|400px|thumb|right|Biochemical Cascade of Catecholamine Synthesis]]

The importance of Somitogenesis and Neural Crest come to a head when neural crest cells must migrate anteriorly past somites 18 to 24, utilising chemoattraction from cells of the extracellular matrix between the neural tube and Adrenal Cortex's primordial mesoderm

Members of the SOX gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands. {{#pmid:18272785|PMID18272785}}

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well. {{#pmid:19396395|PMID19396395}}

===Abnormalities/abnormal development===
----

Abnormalities of the Adrenal Medulla are much less common than its mesoderm-derived shell of the Adrenal Gland. Three of the most notorious abnormalities of the Adrenal Medulla include:

* Pheochromocytomas
* Ganglioneuromas
* Neuroblastomas

Pheochromocytomas (PCCs) are variable neoplasias of the adrenal medulla's chromaffin cells. There are many classifications of PCCs, with autosomal-dominant germ-line mutations and heredities being one of the main causes. Familial pheochromocytoma-paraganglioma (PGL) syndromes exist, with PGL1 having mutations of the SDHD gene, PGL3 being mutated of the SDHC gene and PGL4 having mutation of the SDHB gene. These phenotypically present as extra-adrenal chromaffin bodies, malformation of the adrenal glands themselves, absence of chromaffin bodies and fluctuations in circulating catecholamines. {{#pmid:18021328|PMID18021328}}

Ganglioneuromas (GNs) are classically-benign growths that are very rare and arise from neural crest tissue. They are not circumscribed to the adrenal medulla, but also are found in the sympathetic chain and trunk ganglia. As a result of their scarcity, not much is known about them other than a few aberrant genes and generic clinical presentations. ERBB3, the receptor tyrosine kinas is understood to be important in the development of GNs, as well as an extremely high prevalence of up-regulated GATA3. A key thing to note is also the '''lack''' of N-MYC expression in GNs, which is quite prominent in neuroblastomas and other neoplasias. {{#pmid:29085827|PMID29085827}} {{#pmid:23715162|PMID23715162}}

Neuroblastomas (NBs) are a more aggressive form of cancer, derived from neuroblasts - the precursor cells to neurons. A rather common pediatric cancer, they are often in children who are in risk factor groups such as those with aforementioned familial cancer syndromes, neurofibromatosis-1. These tumours often present with extremely variable catecholamine concentrations, which has implications for blood pressure, heart contractility and much more. Urinary excretion of norepinephrine, homovanillic acid (HVA) and vanilmandelic acid (VMA) can be used to help diagnose a suspected lesion of the adrenal gland, as these chemicals are associated with altered chemical cascades that are suspicious of neuroblastic change. {{#pmid:16372223|PMID16372223}}

Apart from these abnormalities, there are other pathologies that may be connected to the adrenal medulla. One such example is a pathology of the Organ of Zuckerkandl. Also known as the para-aortic body, the Organ of Zuckerkandl is a primarily-gestational organ comprised of chromaffin cells and serves a similar purpose to the adrenal medulla in neonatal life.

===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

====Chromaffin cells====
There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells{{#pmid:19377845|PMID19377845}}. The neural crest cells give rise to chromaffin cells of the adrenal medulla.

=====Rat Models=====
[[File:Adrenal gland.png|300px|thumb|right|3D images showing TH - positive cells accumulating at the cranial and Caudal ends of the adrenal gland.]]
Previous research has reported that nueral crest cells differentiate into chromaffin cells around 19 days of gestation before forming the adrenal medulla{{#pmid:28684471|PMID2868441}}. Past research had also suggested that neural crest derived adrenal gland cells migrate using the sympathetic ganglia to the adrenal gland or preaortic ganglion, following different pathways, to reach their specific destination. However the results have shown that the pathways used to reach its destinations overlapped. This would suggest that there is a possibility of the cells using the same pathway to move from the beginning production to the destination that is the adrenal medulla (for chromaffin cells) and the preaortic ganglion (other cells involved in the sympathetic system).

One particular study done by M.Yamato in 2004, along with his fellow scientists attempted to study the migration of neural crest cells in Wistar rats. In order to observe the formation adrenal medulla from the neural crest cells during the embryonic period, Yamato used anti - tyrosine hydroxylase (TH) antiserum injected into the rat embryos between 13-17 days of gestation. The anti - TH antiserum stain allows the scientists to visualize the neural crest cells under a light microscope. Later three dimensional images were created. From the images observed between 13 to 15 days of gestation, the TH - positive cells can be seen to move from the dorsal to the adrenal primordium{{#pmid:15240937|PMID15240937}}. After 16 days it was observed that a capsule had formed in some parts and TH - positive cells had penetrated the adrenal gland{{#pmid:15240937|PMID15240937}}. At seventeen days, TH - positive cells can be seen collecting at the medial part of the adrenal gland. The reconstructed images also shows that at the later stages during the 16-17 days of gestation, the accumulation of TH - positive cells grow and in combination with cell division leads to the formation of the adrenal medulla.

=====Chicken models=====
Chicken and rat models are often the most commonly used models when dealing with neural crest cells. A particle review article, collates multiple researchers results and presents evidence to discuss previous information suggesting that sympathetic neurons and chromaffin cells do not share a common progenitor{{#pmid:3693940|PMID3693940}}. The relevant study involved the use of cell cultures, Sympathoadrneal (SA) progenitor cells from embryonic(from chick embryos) and eary developmental stages were able to be procured. From these cultures it was easy to identify that glucocorticoids were crucial in the differentiation of SA cells into their derivatives, sympathetic neurons and chromaffin cells.

[[File:Expression of BMP protein 4 .jpg|300px|thumb|right|Shows the movement of the chromaffin progenitors moving from each stage of development. sg: sympathetic ganglia ac:adrenal cortical region ag: adrenal gland da: dorsal aortic region]]

Another study conducted deals with the role of the bone morphogenetic protein(BMP-4) and its importance in the development of the adrenal medullary cells, chromaffin cells{{#pmid:18945349|PMID18945349}}. Previous research had shown that BMP - 4 a growth factor is plays an important role in the regulation of chromaffin cell production{{#pmid:10679774|PMID10679774}}. The researchers incubated chick embryos for 3 - 9 embryonic days and dissected them to be used for tissue cultures. Embryonic day 8 chick embryos had BMP - 4 overexpressing cells implanted in the sympathetic ganglia area, as well as other neurons which contained chromaffin like cells. What was observed was an increase in size and numbers of 'chromaffin' granules{{#pmid:18945349|PMID18945349}}. As a result it was concluded that although BMP - 4 promotes certain chromaffin traits, it does not have the capability to convert sympathetic neurons into a chromaffin type cell.

===Current research (labs)===
----

==== Generation of Adrenal Chromaffin-like Cells from Human Pluripotent Stem Cells====

As explained above the adrenal medulla plays an important part in the autonomic system of an adult human. The chromaffin cells, in particular, are important neural crest derived cell that is closely related to the adrenal medulla. Previous findings have focused specifically on the mechanisms controlling the neural crest cell migration and how these cells go on to form the different derivatives in their particular destinations in the embryo. For example, as previously explained studies have shown that chromaffin cells have been observed to move to the adrenal gland to form the medulla of the adrenal gland. This report goes through a recent study that involves the adrenal medullary cells, in particular chromaffin cells, and their potential to be used to model certain pathological diseases related to these cells. This is part of a study that also involves neural crest cells and their ability to differentiate into multiple different types of cells<ref>Lumb, R., & Schwarz, Q. (2015). Sympathoadrenal neural crest cells: The known, unknown and forgotten?. Development, Growth & Differentiation, 57(2), 146-157. doi: 10.1111/dgd.12189</ref>. Neural crest cells and SAPs from human embryonic cells and induced pluripotent stem cells were generated to be used in the experiment. By exposing the pluripotent stem cells to BMP4 in vitro, results showed that these cells would 'upregulate' the chromaffin cell - specific marker PMNT (an enzyme that synthesizes adrenaline). Furthermore when the cells from human embryos were implanted into avian embryos, there was a visible potential for the human cells to differentiate into cells that expressed the chromaffin cell markers{{#pmid:5768882|PMID5768882}}.

Link to article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/

====Multipotent Peripheral Glial Cells Generate Neuroendocrine Cells of the Adrenal Medulla====

Similar to the first study, this one also focuses on the chromaffin cells and their relationship to the adrenal medulla. Chromaffin cells often represent the main endocrine component that is believed to differentiate from neural crest cells{{#pmid:28684471|PMID28684471}}. The study focuses specifically on the idea that previous research has suggested that nerve - associated schwann cell precursor is a progenitor of chromaffin cells. What the findings suggested was that peripheral nerves provided migration routes for the progenitors. This is backed up by the results, a high concentration of chromaffin cells can be found being derived from the nerve, as nerve ablated mice in the experiment showed a large difference of 78% less cells compared to the control. Other than this, the study also brought to light the proliferative potential of the cells from nerves, with different other cell types being discovered as well (including cells such as parasympathetic{{#pmid:24925912|PMID24925912}} and melanocytes {{#pmid:19837037 |PMID19837037}}). The findings would provide useful information into further understanding the adrenal gland and its embryonic origins (as there is still much to learn regarding the formation of the adrenal medulla) but also pathological diseases such as neuroblastoma and pheochromatocytoma which are most common in the adrenal glandular region {{#pmid:23106811|PMID23106811}}.

Link to article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013038/

===Glossary===
----
*BMP4 - Bone Morphogenic Protein 4
*DOPA - Dihydroxyphenylalanine
*GATA3 - Transcription factor 3 for GATA gene
*GN - Ganglioneuroma
*GRN - Gene Regulatory Network
*HNK1 - Human Natural Killer 1
*HVA - Homovanillic Acid
*L-DOPA - L-3,4-dihydroxyphenylalanine
*NB - Neuroblastoma
*PAX - Paired Box
*PCC - Pheochromocytoma
*PGL - Pheochromocytoma Paraganglioma
*PNMT - phenylethanolamine-N-methyltransferase
*SGC - Small Granule Containing cells
*SOX - Sry Box
*TH - Tyrosine Hydroxylase
*VMA -Vanilmandelic Acid

===Reference list===

2018 Group Project 1

2018-10-16T01:42:12Z

Z5113627: /* Glossary */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===

----

The neural crest of an embryo migrates and differentiates to form various components of the body. This transient population of pluripotent stem-cells give rise to many complex and different structures across the adult by chemical signalling. One of these tissues is the medulla of the adrenal gland which is involved in the production of epinephrine and norepinephrine. This project will comprehensively outline the history of neural crest research, the embryonic developmental time course, tissue and organ structure, molecular mechanisms, abnormalities, animal models and current research.

===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
[[File:NC Location.jpg|right|450px|thumb|The neural crest]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb|465px]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniably lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Embryonic origins===
----
[[File:Trunk_NCC_migration.jpg|left|450px|thumb|Trunk NCC migration]]
The adrenal gland is made up of the adrenal cortex and adrenal medulla, which both have different embryonic origins. The adrenal medulla arises from the neural crest tissue, found near the level of the coeliac plexus & sympathetic ganglion at somites 18-24 {{#pmid:16124976|PMID16124976}}. Specifically, this neural crest tissue comes from the trunk neural crest cells (see above figure to determine the approximate location in an embryo) <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
The trunk neural crest coordinates the development of the endocrine system, secretory cells, the peripheral nervous system and, to some degree, skeletal development, as well as innervation of the intestine {{#pmid: 28287247|PMID 28287247}}. The trunk neural cells arise caudally, undergo an epithelial to mesenchymal transition and follow three migratory pathways {{#pmid:20399766|PMID20399766}}.
[[File:Differentiation_of_NCC.jpg|left|580px|thumb|Differentiation of chromaffin cells]]
- A dorsolateral pathway (between ectoderm and somites), these become melanocytes, travel up to the point of the dermis and become a major part of the hair follicles and skin <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
- A ventrolateral pathway (through the somites)
- A ventromedial pathway (between neural tube and posterior schlerotome){{#pmid:20399766|PMID20399766}}.

Migration of neural crest cells from the sympathetic ganglion is what leads to the development of the adrenal medulla. In week 8 of development, immature cells called neuroblasts migrate through to the inner portion of the medulla, where they become the adrenal medulla {{#pmid:19683477|PMID19683477}}. Chromaffin cells are neuroendocrine cells and are found in the sympathetic ganglia and make up the majority of the adrenal medulla{{#pmid:19683477|PMID19683477}}. They synthesise and release a range of hormones in the body and arise from the temporary neural crest. The term chromaffin was inspired by the staining capacity of these cells when they came into contact with chrome salts. They make, store, export and use catecholamines, responsible for making noradrenaline and originate at the caudal region of somites 18-24 of the neural crest, also known as the adrenomedullary region {{#pmid:19683477|PMID19683477}}.

For cells to leave the neural crest and begin their migration, certain conditions need to be met, that is, the cells need to be loosely connected, their tight junctions becoming relaxed, initiated by "Slug protein" and a loss of N-Cadherin which also leads to the loosening of these junctions. The surrounding matrix as well as chemotactic and stem cell factors of the neural tube are then what dictates how the neural crest cells move, some proteins stopping their migration to that area and others encouraging the movement <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. After splitting apart, the first neural crest cells move ventrally and pass into the spaces between the somites and then, through the anterior portions of each segment until they arrive at the para-aortic sites, where they become the cells of the sympathetic ganglia and the adrenal medulla {{#pmid:19683477|PMID19683477}}. BMP-4 (bone morphogenetic protein 4) then acts on these neural crest cells, preventing them from becoming cells that have a neural function and causing them to become chromaffin cells at the adrenal medulla. Glucocorticoids then play a role in maintenance of chromaffin cells in postnatal life, this was only found recently, as previously it was thought that glucocorticoids were responsible entirely for the differentiation of neural crest cells into chromaffin, or adrenomedullary cells {{#pmid:23220335|PMID23220335}}.

===Anatomy and Functions===

----

====Anatomy and Histology====

The adrenal medulla makes up the inner section of the adrenal glands, and is surrounded by the cortex, and a connective tissue capsule. It lies in the centre of the gland and it rarely measures no more than 2mm in thickness {{#pmid:21107679|PMID21107679}}. The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The adrenal medulla contains secretory cells called chromaffin cells due to the agents they produce when oxidised, such as chromate {{#pmid:11215683|PMID11215683}}. These cells secrete epinephrine, norepinephrine, chromogranin and neuropeptides in response to various substances such as acetylcholine <ref name="PMID11215683"/>. [[File:ADRENAL MEDULLA .jpg|600px|thumb|right|Adrenal Medulla Histology]]

There are many types of highly differentiated cells in the adult adrenal medulla:
- Epinephrine cells (90% of all chromaffin cells) {{#pmid:24715564|PMID24715564}}
- Norepinephrine cells (10% of all chromaffin cells) <ref name="PMID24715564"/>
- Small granule-containing cells (SGCs) <ref name="PMID11215683"/>

These cells also synthesise, store and secrete catecholamines through controlled and regulated pathways <ref name="PMID24715564"/>, such as various peptides like substance P and neurotensin.These cells have unique neuroendocrine characteristics as a result of their neural-crest origin. They receive preganglionic innervation by thoracic splanchnic nerves, and could almost be considered a specialised sympathetic ganglion. With postganglgionic bodies, cells of the medulla are densely clustered around their vasculature for the secretion of hormones into the bloodstream to moderate the concentration of epinephrine and norepinephrine. The adrenal medulla also contains presynaptic sympathetic ganglion cells <ref name="PMID11215683"/>. The small granule-containing cells are usually found in clusters whereas, the ganglion cells are found either individually or in clusters, usually dispersed among the chromaffin cells or among the nerve fibres {{#pmid:18021328|PMID18021328}}. During embryonic development (around weeks 9-12), in contrast to the developing adrenal cortex, the medulla does not show evidence of an organised structure other than a small cluster of cells scattered throughout its cortex {{#pmid:30247985|PMID30247985}}.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus. {{#pmid:11215683|PMID11215683}}

[[File:Dd.jpg|400px|thumb|right|Adult Adrenal Glands in situ]]
----
====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses. {{#pmid:19396395|PMID19396395}}

'''Adult Function'''

While the adrenal cortex releases glucocorticoids in response to long term stress, the adrenal medulla releases its hormones in response to short-term, acute stress. The adrenal medulla contains the neuroendocrine chromaffin cells which are responsible for secreting adrenaline and noradrenaline. The function of these hormones is primarily to maintain the body’s homeostasis, especially of the internal organs, and to properly activate the autonomic stress response, more commonly known as the ‘fight or flight’ response {{#pmid:30237243|PMID30237243}}. Thus the function of the medulla includes signalling the liver and skeletal muscles to convert glycogen into glucose for increased energy. This results in increased blood glucose levels. These hormones also increase the heart rate, pulse and blood pressure in preparation for the fight or flight response. In addition to this, these hormones dilate the lung airways and prompt vasodilation to further increase oxygenation of important organs such as the lung, brain and heart. Vasoconstriction of blood vessels is also prompted to other less essential organs such as the bladder and the digestive system.

Other effects also include pupil dilation, dry mouth and a loss in peripheral vision <ref name="PMID18021328"/>. Paramount to the correct response of chromaffin cells is the synaptic connection of the preganglionic cells which originate from the central nervous system and project axons into the adrenal medulla. While this is a very important relationship, the mechanisms of this remains unknown <ref name="PMID30237243"/>. In addition to the release of catecholamines, cells in the medulla also release peptides through the process of exocytosis from chromaffin granules, to help regulate blood pressure and regulation throughout the body. These peptides also regulate the release of adrenaline and noradrenaline, blood vessel contraction and the immune response <ref name="PMID18021328"/>.

'''Embryonic function'''

The current knowledge about the development of the adrenal gland is limited, with nearly all models being from animals, and very limited functional data available from human fetal adrenals <ref name="PMID30247985"/>. Thus for these reasons, there is scarce information available on the embryonic adrenal medullary functions. Nevertheless, there is accumulating evidence that the catecholamines in the fetal adrenal medulla plays an important role in the time of delivery by controlling thermogenesis and heart regulation {{#pmid:6998630|PMID6998630}}.

The hormones released by the medulla during birth also play a key role for the newborn’s adaptation to extrauterine life. Despite the immaturity of the adrenal medulla at birth, it is known that respiratory, metabolic and cardiovascular changes during delivery are dependent on the adrenomedullary hormones {{#pmid:3280659|PMID3280659}}. Experimental data from human and animal fetal research shows that the fetal sympathoadrenal system, consisting of the adrenal medulla, sympathetic neurons and chromaffin tissue work together to maintain fetal homeostasis {{#pmid:6346884|PMID6346884}}. The adrenal medulla thus appears to provide vital physiological functions for fetal and neonatal survival, especially during birth.

----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

The 'story' of the Adrenal Medulla's neural crest tissue begins at the process of neurulation, the formation of the neural tube from the folding neural plate, which is comprised of developing ectoderm which is opposite to the primitive streak. It is here that several key chemical players are at work. The classic interpretation of Sonic Hedgehog (Shh) and Wnt signalling pathways as the only mediators here, has been shown to be incorrect. Research has uncovered other signallers such as:

*Bone-Morphogenic-Protein-4 (BMP4) for the regional expression of nervous system distinctions in the growing neural plate. This maintains two important embryonic trancription factors known as Paired-Box (PAX) Genes 3 and 7 which can allow for expression of neural crest markers HNK-1, SRY-Box (SOX) 8, 9 and 10 as the neural tube closes and the neural crest delaminates from the folding. {{#pmid:16688176|PMID16688176}}

*Slug via Wnt signalling, this allows for the loosening of gap junctions in the extracellular matrix surrounding the newly-formed neural tube and trunk of the embryo. This extracellular matrix has chemo-attractant molecules

[[File:Catecholamine_Synthesis.jpg|400px|thumb|right|Biochemical Cascade of Catecholamine Synthesis]]

The importance of Somitogenesis and Neural Crest come to a head when neural crest cells must migrate anteriorly past somites 18 to 24

Members of the SOX gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands. {{#pmid:18272785|PMID18272785}}

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well. {{#pmid:19396395|PMID19396395}}

===Abnormalities/abnormal development===
----

Abnormalities of the Adrenal Medulla are much less common than its mesoderm-derived shell of the Adrenal Gland. Three of the most notorious abnormalities of the Adrenal Medulla include:

* Pheochromocytomas
* Ganglioneuromas
* Neuroblastomas

Pheochromocytomas (PCCs) are variable neoplasias of the adrenal medulla's chromaffin cells. There are many classifications of PCCs, with autosomal-dominant germ-line mutations and heredities being one of the main causes. Familial pheochromocytoma-paraganglioma (PGL) syndromes exist, with PGL1 having mutations of the SDHD gene, PGL3 being mutated of the SDHC gene and PGL4 having mutation of the SDHB gene. These phenotypically present as extra-adrenal chromaffin bodies, malformation of the adrenal glands themselves, absence of chromaffin bodies and fluctuations in circulating catecholamines. {{#pmid:18021328|PMID18021328}}

Ganglioneuromas (GNs) are classically-benign growths that are very rare and arise from neural crest tissue. They are not circumscribed to the adrenal medulla, but also are found in the sympathetic chain and trunk ganglia. As a result of their scarcity, not much is known about them other than a few aberrant genes and generic clinical presentations. ERBB3, the receptor tyrosine kinas is understood to be important in the development of GNs, as well as an extremely high prevalence of up-regulated GATA3. A key thing to note is also the '''lack''' of N-MYC expression in GNs, which is quite prominent in neuroblastomas and other neoplasias. {{#pmid:29085827|PMID29085827}} {{#pmid:23715162|PMID23715162}}

Neuroblastomas (NBs) are a more aggressive form of cancer, derived from neuroblasts - the precursor cells to neurons. A rather common pediatric cancer, they are often in children who are in risk factor groups such as those with aforementioned familial cancer syndromes, neurofibromatosis-1. These tumours often present with extremely variable catecholamine concentrations, which has implications for blood pressure, heart contractility and much more. Urinary excretion of norepinephrine, homovanillic acid (HVA) and vanilmandelic acid (VMA) can be used to help diagnose a suspected lesion of the adrenal gland, as these chemicals are associated with altered chemical cascades that are suspicious of neuroblastic change. {{#pmid:16372223|PMID16372223}}

Apart from these abnormalities, there are other pathologies that may be connected to the adrenal medulla. One such example is a pathology of the Organ of Zuckerkandl. Also known as the para-aortic body, the Organ of Zuckerkandl is a primarily-gestational organ comprised of chromaffin cells and serves a similar purpose to the adrenal medulla in neonatal life.

===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

====Chromaffin cells====
There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells{{#pmid:19377845|PMID19377845}}. The neural crest cells give rise to chromaffin cells of the adrenal medulla.

=====Rat Models=====
[[File:Adrenal gland.png|300px|thumb|right|3D images showing TH - positive cells accumulating at the cranial and audal ends of the adrenal gland. A. A observation of adrenal gland and surrounding structures (at 17 days of gestation). B. Enhanced image to further focus on the dark TH - positive cells. C. Image with the other structures removed.]]
Previous research has reported that nueral crest cells differentiate into chromaffin cells around 19 days of gestation before forming the adrenal medulla{{#pmid:28684471|PMID2868441}}. Past research had also suggested that neural crest derived adrenal gland cells migrate using the sympathetic ganglia to the adrenal gland or preaortic ganglion, following different pathways, to reach their specific destination. However the results have shown that the pathways used to reach its destinations overlapped. This would suggest that there is a possibility of the cells using the same pathway to move from the beginning production to the destination that is the adrenal medulla (for chromaffin cells) and the preaortic ganglion (other cells involved in the sympathetic system).

One particular study done by M.Yamato in 2004, along with his fellow scientists attempted to study the migration of neural crest cells in Wistar rats. In order to observe the formation adrenal medulla from the neural crest cells during the embryonic period, Yamato used anti - tyrosine hydroxylase (TH) antiserum injected into the rat embryos between 13-17 days of gestation. The anti - TH antiserum stain allows the scientists to visualize the neural crest cells under a light microscope. Later three dimensional images were created. From the images observed between 13 to 15 days of gestation, the TH - positive cells can be seen to move from the dorsal to the adrenal primordium{{#pmid:15240937|PMID15240937}}. After 16 days it was observed that a capsule had formed in some parts and TH - positive cells had penetrated the adrenal gland{{#pmid:15240937|PMID15240937}}. At seventeen days, TH - positive cells can be seen collecting at the medial part of the adrenal gland. The reconstructed images also shows that at the later stages during the 16-17 days of gestation, the accumulation of TH - positive cells grow and in combination with cell division leads to the formation of the adrenal medulla.

=====Chicken models=====
Chicken and rat models are often the most commonly used models when dealing with neural crest cells. In this particular review, collates multiple researchers results and presents evidence to discuss previous information suggesting that sympathetic neurons and chromaffin cells do not share a common progenitor{{#pmid:3693940|PMID3693940}}. The relevant study involved the use of cell cultures, Sympathoadrneal (SA) progenitor cells from embryonic(from chick embryos) and eary developmental stages were able to be procured. From these cultures it was easy to identify that glucocorticoids were crucial in the differentiation of SA cells into their derivatives, sympathetic neurons and chromaffin cells.

[[File:Expression of BMP protein 4 .jpg|300px|thumb|right|Expression of BMP - 4 in the adrenal cortex at developmental stages. Shows the movement of the chromaffin progenitors moving from each stage of development. A-D: collection of progenitors outside E-H: cells have begun to penetrate the adrenal cortical region I-L: chromaffin cells have completely intergrated intergreted within the gland sg: sympathetic ganglia ac:adrenal cortical region ag: adrenal gland da: dorsal aortic region]]

Another study conducted deals with the role of the bone morphogenetic protein(BMP-4) and its importance in the development of the adrenal medullary cells, chromaffin cells{{#pmid:18945349|PMID18945349}}. Previous research had shown that BMP - 4 a growth factor is plays an important role in the regulation of chromaffin cell production{{#pmid:10679774|PMID10679774}}. The researchers incubated chick embryos for 3 - 9 embryonic days and dissected them to be used for tissue cultures. Embryonic day 8 chick embryos had BMP - 4 overexpressing cells implanted in the sympathetic ganglia area, as well as other neurons which contained chromaffin like cells. What was observed was an increase in size and numbers of 'chromaffin' granules{{#pmid:18945349|PMID18945349}}. As a result it was concluded that although BMP - 4 promotes certain chromaffin traits, it does not have the capability to convert sympathetic neurons into a chromaffin type cell.

===Current research (labs)===
----

==== Generation of Adrenal Chromaffin-like Cells from Human Pluripotent Stem Cells====

As explained above the adrenal medulla plays an important part in the autonomic system of an adult human. The chromaffin cells, in particular, are important neural crest derived cell that is closely related to the adrenal medulla. Previous findings have focused specifically on the mechanisms controlling the NCC migration and how these cells go on to form the different derivatives in their particular destinations in the embryo. For example, as previously explained studies have shown that chromaffin cells have been observed to move to the adrenal gland to form the medulla of the adrenal gland. This report goes through a recent study that involves the adrenal medullary cells, in particular chromaffin cells, and their potential to be used to model certain pathological diseases related to these cells. This is part of a study that also involves neural crest cells and their ability to differentiate into multiple different types of cells<ref>Lumb, R., & Schwarz, Q. (2015). Sympathoadrenal neural crest cells: The known, unknown and forgotten?. Development, Growth & Differentiation, 57(2), 146-157. doi: 10.1111/dgd.12189</ref>. Neural crest cells and SAPs from human embryonic cells and induced pluripotent stem cells were generated to be used in the experiment. By exposing the pluripotent stem cells to BMP4 in vitro, results showed that these cells would 'upregulate' the chromaffin cell - specific marker PMNT (an enzyme that synthesizes adrenaline). Furthermore when the cells from human embryos were implanted into avian embryos, there was a visible potential for the human cells to differentiate into cells that expressed the chromaffin cell markers{{#pmid:5768882|PMID5768882}}.

====Multipotent Peripheral Glial Cells Generate Neuroendocrine Cells of the Adrenal Medulla====

Similar to the first study, this one also focuses on the chromaffin cells and their relationship to the adrenal medulla. Chromaffin cells often represent the main endocrine component that is believed to differentiate from neural crest cells{{#pmid:28684471|PMID28684471}}. The study focuses specifically on the idea that previous research has suggested that nerve - associated schwann cell precursor is a progenitor of chromaffin cells. What the findings suggested was that peripheral nerves provided migration routes for the progenitors. This is backed up by the results, a high concentration of chromaffin cells can be found being derived from the nerve, as nerve ablated mice in the experiment showed a large difference of 78% less cells compared to the control. Other than this, the study also brought to light the proliferative potential of the cells from nerves, with different other cell types being discovered as well (including cells such as parasympathetic{{#pmid:24925912|PMID24925912}} and melanocytes {{#pmid:19837037 |PMID19837037}}). The findings would provide useful information into further understanding the adrenal gland and its embryonic origins (as there is still much to learn regarding the formation of the adrenal medulla) but also pathological diseases such as neuroblastoma and pheochromatocytoma which are most common in the adrenal glandular region {{#pmid:23106811|PMID23106811}}.

===Glossary===
----
*BMP4 - Bone Morphogenic Protein 4
*DOPA - Dihydroxyphenylalanine
*GATA3 - Transcription factor 3 for GATA gene
*GN - Ganglioneuroma
*GRN - Gene Regulatory Network
*HNK1 - Human Natural Killer 1
*HVA - Homovanillic Acid
*L-DOPA - L-3,4-dihydroxyphenylalanine
*NB - Neuroblastoma
*PAX - Paired Box
*PCC - Pheochromocytoma
*PGL - Pheochromocytoma Paraganglioma
*SGC - Small Granule Containing cells
*SOX - Sry Box
*TH - Tyrosine Hydroxylase
*VMA -Vanilmandelic Acid

===Reference list===

2018 Group Project 1

2018-10-16T01:37:40Z

Z5113627: /* Glossary */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===

----

The neural crest of an embryo migrates and differentiates to form various components of the body. This transient population of pluripotent stem-cells give rise to many complex and different structures across the adult by chemical signalling. One of these tissues is the medulla of the adrenal gland which is involved in the production of epinephrine and norepinephrine. This project will comprehensively outline the history of neural crest research, the embryonic developmental time course, tissue and organ structure, molecular mechanisms, abnormalities, animal models and current research.

===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
[[File:NC Location.jpg|right|450px|thumb|The neural crest]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb|465px]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniably lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Embryonic origins===
----
[[File:Trunk_NCC_migration.jpg|left|450px|thumb|Trunk NCC migration]]
The adrenal gland is made up of the adrenal cortex and adrenal medulla, which both have different embryonic origins. The adrenal medulla arises from the neural crest tissue, found near the level of the coeliac plexus & sympathetic ganglion at somites 18-24 {{#pmid:16124976|PMID16124976}}. Specifically, this neural crest tissue comes from the trunk neural crest cells (see above figure to determine the approximate location in an embryo) <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
The trunk neural crest coordinates the development of the endocrine system, secretory cells, the peripheral nervous system and, to some degree, skeletal development, as well as innervation of the intestine {{#pmid: 28287247|PMID 28287247}}. The trunk neural cells arise caudally, undergo an epithelial to mesenchymal transition and follow three migratory pathways {{#pmid:20399766|PMID20399766}}.
[[File:Differentiation_of_NCC.jpg|left|580px|thumb|Differentiation of chromaffin cells]]
- A dorsolateral pathway (between ectoderm and somites), these become melanocytes, travel up to the point of the dermis and become a major part of the hair follicles and skin <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
- A ventrolateral pathway (through the somites)
- A ventromedial pathway (between neural tube and posterior schlerotome){{#pmid:20399766|PMID20399766}}.

Migration of neural crest cells from the sympathetic ganglion is what leads to the development of the adrenal medulla. In week 8 of development, immature cells called neuroblasts migrate through to the inner portion of the medulla, where they become the adrenal medulla {{#pmid:19683477|PMID19683477}}. Chromaffin cells are neuroendocrine cells and are found in the sympathetic ganglia and make up the majority of the adrenal medulla{{#pmid:19683477|PMID19683477}}. They synthesise and release a range of hormones in the body and arise from the temporary neural crest. The term chromaffin was inspired by the staining capacity of these cells when they came into contact with chrome salts. They make, store, export and use catecholamines, responsible for making noradrenaline and originate at the caudal region of somites 18-24 of the neural crest, also known as the adrenomedullary region {{#pmid:19683477|PMID19683477}}.

For cells to leave the neural crest and begin their migration, certain conditions need to be met, that is, the cells need to be loosely connected, their tight junctions becoming relaxed, initiated by "Slug protein" and a loss of N-Cadherin which also leads to the loosening of these junctions. The surrounding matrix as well as chemotactic and stem cell factors of the neural tube are then what dictates how the neural crest cells move, some proteins stopping their migration to that area and others encouraging the movement <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. After splitting apart, the first neural crest cells move ventrally and pass into the spaces between the somites and then, through the anterior portions of each segment until they arrive at the para-aortic sites, where they become the cells of the sympathetic ganglia and the adrenal medulla {{#pmid:19683477|PMID19683477}}. BMP-4 (bone morphogenetic protein 4) then acts on these neural crest cells, preventing them from becoming cells that have a neural function and causing them to become chromaffin cells at the adrenal medulla. Glucocorticoids then play a role in maintenance of chromaffin cells in postnatal life, this was only found recently, as previously it was thought that glucocorticoids were responsible entirely for the differentiation of neural crest cells into chromaffin, or adrenomedullary cells {{#pmid:23220335|PMID23220335}}.

===Anatomy and Functions===

----

====Anatomy and Histology====

The adrenal medulla makes up the inner section of the adrenal glands, and is surrounded by the cortex, and a connective tissue capsule. It lies in the centre of the gland and it rarely measures no more than 2mm in thickness {{#pmid:21107679|PMID21107679}}. The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The adrenal medulla contains secretory cells called chromaffin cells due to the agents they produce when oxidised, such as chromate {{#pmid:11215683|PMID11215683}}. These cells secrete epinephrine, norepinephrine, chromogranin and neuropeptides in response to various substances such as acetylcholine <ref name="PMID11215683"/>. [[File:ADRENAL MEDULLA .jpg|600px|thumb|right|Adrenal Medulla Histology]]

There are many types of highly differentiated cells in the adult adrenal medulla:
- Epinephrine cells (90% of all chromaffin cells) {{#pmid:24715564|PMID24715564}}
- Norepinephrine cells (10% of all chromaffin cells) <ref name="PMID24715564"/>
- Small granule-containing cells (SGCs) <ref name="PMID11215683"/>

These cells also synthesise, store and secrete catecholamines through controlled and regulated pathways <ref name="PMID24715564"/>, such as various peptides like substance P and neurotensin.These cells have unique neuroendocrine characteristics as a result of their neural-crest origin. They receive preganglionic innervation by thoracic splanchnic nerves, and could almost be considered a specialised sympathetic ganglion. With postganglgionic bodies, cells of the medulla are densely clustered around their vasculature for the secretion of hormones into the bloodstream to moderate the concentration of epinephrine and norepinephrine. The adrenal medulla also contains presynaptic sympathetic ganglion cells <ref name="PMID11215683"/>. The small granule-containing cells are usually found in clusters whereas, the ganglion cells are found either individually or in clusters, usually dispersed among the chromaffin cells or among the nerve fibres {{#pmid:18021328|PMID18021328}}. During embryonic development (around weeks 9-12), in contrast to the developing adrenal cortex, the medulla does not show evidence of an organised structure other than a small cluster of cells scattered throughout its cortex {{#pmid:30247985|PMID30247985}}.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus. {{#pmid:11215683|PMID11215683}}

[[File:Dd.jpg|400px|thumb|right|Adult Adrenal Glands in situ]]
----
====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses. {{#pmid:19396395|PMID19396395}}

'''Adult Function'''

While the adrenal cortex releases glucocorticoids in response to long term stress, the adrenal medulla releases its hormones in response to short-term, acute stress. The adrenal medulla contains the neuroendocrine chromaffin cells which are responsible for secreting adrenaline and noradrenaline. The function of these hormones is primarily to maintain the body’s homeostasis, especially of the internal organs, and to properly activate the autonomic stress response, more commonly known as the ‘fight or flight’ response {{#pmid:30237243|PMID30237243}}. Thus the function of the medulla includes signalling the liver and skeletal muscles to convert glycogen into glucose for increased energy. This results in increased blood glucose levels. These hormones also increase the heart rate, pulse and blood pressure in preparation for the fight or flight response. In addition to this, these hormones dilate the lung airways and prompt vasodilation to further increase oxygenation of important organs such as the lung, brain and heart. Vasoconstriction of blood vessels is also prompted to other less essential organs such as the bladder and the digestive system.

Other effects also include pupil dilation, dry mouth and a loss in peripheral vision <ref name="PMID18021328"/>. Paramount to the correct response of chromaffin cells is the synaptic connection of the preganglionic cells which originate from the central nervous system and project axons into the adrenal medulla. While this is a very important relationship, the mechanisms of this remains unknown <ref name="PMID30237243"/>. In addition to the release of catecholamines, cells in the medulla also release peptides through the process of exocytosis from chromaffin granules, to help regulate blood pressure and regulation throughout the body. These peptides also regulate the release of adrenaline and noradrenaline, blood vessel contraction and the immune response <ref name="PMID18021328"/>.

'''Embryonic function'''

The current knowledge about the development of the adrenal gland is limited, with nearly all models being from animals, and very limited functional data available from human fetal adrenals <ref name="PMID30247985"/>. Thus for these reasons, there is scarce information available on the embryonic adrenal medullary functions. Nevertheless, there is accumulating evidence that the catecholamines in the fetal adrenal medulla plays an important role in the time of delivery by controlling thermogenesis and heart regulation {{#pmid:6998630|PMID6998630}}.

The hormones released by the medulla during birth also play a key role for the newborn’s adaptation to extrauterine life. Despite the immaturity of the adrenal medulla at birth, it is known that respiratory, metabolic and cardiovascular changes during delivery are dependent on the adrenomedullary hormones {{#pmid:3280659|PMID3280659}}. Experimental data from human and animal fetal research shows that the fetal sympathoadrenal system, consisting of the adrenal medulla, sympathetic neurons and chromaffin tissue work together to maintain fetal homeostasis {{#pmid:6346884|PMID6346884}}. The adrenal medulla thus appears to provide vital physiological functions for fetal and neonatal survival, especially during birth.

----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

The 'story' of the Adrenal Medulla's neural crest tissue begins at the process of neurulation, the formation of the neural tube from the folding neural plate, which is comprised of developing ectoderm which is opposite to the primitive streak. It is here that several key chemical players are at work. The classic interpretation of Sonic Hedgehog (Shh) and Wnt signalling pathways as the only mediators here, has been shown to be incorrect. Research has uncovered other signallers such as:

*Bone-Morphogenic-Protein-4 (BMP4) for the regional expression of nervous system distinctions in the growing neural plate. This maintains two important embryonic trancription factors known as Paired-Box (PAX) Genes 3 and 7 which can allow for expression of neural crest markers HNK-1, SRY-Box (SOX) 8, 9 and 10 as the neural tube closes and the neural crest delaminates from the folding. {{#pmid:16688176|PMID16688176}}

*Slug via Wnt signalling, this allows for the loosening of gap junctions in the extracellular matrix surrounding the newly-formed neural tube and trunk of the embryo. This extracellular matrix has chemo-attractant molecules

[[File:Catecholamine_Synthesis.jpg|400px|thumb|right|Biochemical Cascade of Catecholamine Synthesis]]

The importance of Somitogenesis and Neural Crest come to a head when neural crest cells must migrate anteriorly past somites 18 to 24

Members of the SOX gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands. {{#pmid:18272785|PMID18272785}}

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well. {{#pmid:19396395|PMID19396395}}

===Abnormalities/abnormal development===
----

Abnormalities of the Adrenal Medulla are much less common than its mesoderm-derived shell of the Adrenal Gland. Three of the most notorious abnormalities of the Adrenal Medulla include:

* Pheochromocytomas
* Ganglioneuromas
* Neuroblastomas

Pheochromocytomas (PCCs) are variable neoplasias of the adrenal medulla's chromaffin cells. There are many classifications of PCCs, with autosomal-dominant germ-line mutations and heredities being one of the main causes. Familial pheochromocytoma-paraganglioma (PGL) syndromes exist, with PGL1 having mutations of the SDHD gene, PGL3 being mutated of the SDHC gene and PGL4 having mutation of the SDHB gene. These phenotypically present as extra-adrenal chromaffin bodies, malformation of the adrenal glands themselves, absence of chromaffin bodies and fluctuations in circulating catecholamines. {{#pmid:18021328|PMID18021328}}

Ganglioneuromas (GNs) are classically-benign growths that are very rare and arise from neural crest tissue. They are not circumscribed to the adrenal medulla, but also are found in the sympathetic chain and trunk ganglia. As a result of their scarcity, not much is known about them other than a few aberrant genes and generic clinical presentations. ERBB3, the receptor tyrosine kinas is understood to be important in the development of GNs, as well as an extremely high prevalence of up-regulated GATA3. A key thing to note is also the '''lack''' of N-MYC expression in GNs, which is quite prominent in neuroblastomas and other neoplasias. {{#pmid:29085827|PMID29085827}} {{#pmid:23715162|PMID23715162}}

Neuroblastomas (NBs) are a more aggressive form of cancer, derived from neuroblasts - the precursor cells to neurons. A rather common pediatric cancer, they are often in children who are in risk factor groups such as those with aforementioned familial cancer syndromes, neurofibromatosis-1. These tumours often present with extremely variable catecholamine concentrations, which has implications for blood pressure, heart contractility and much more. Urinary excretion of norepinephrine, homovanillic acid (HVA) and vanilmandelic acid (VMA) can be used to help diagnose a suspected lesion of the adrenal gland, as these chemicals are associated with altered chemical cascades that are suspicious of neuroblastic change. {{#pmid:16372223|PMID16372223}}

Apart from these abnormalities, there are other pathologies that may be connected to the adrenal medulla. One such example is a pathology of the Organ of Zuckerkandl. Also known as the para-aortic body, the Organ of Zuckerkandl is a primarily-gestational organ comprised of chromaffin cells and serves a similar purpose to the adrenal medulla in neonatal life.

===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

====Chromaffin cells====
There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells{{#pmid:19377845|PMID19377845}}. The neural crest cells give rise to chromaffin cells of the adrenal medulla.

=====Rat Models=====
[[File:Adrenal gland.png|300px|thumb|right|3D images showing TH - positive cells accumulating at the cranial and audal ends of the adrenal gland. A. A observation of adrenal gland and surrounding structures (at 17 days of gestation). B. Enhanced image to further focus on the dark TH - positive cells. C. Image with the other structures removed.]]
Previous research has reported that nueral crest cells differentiate into chromaffin cells around 19 days of gestation before forming the adrenal medulla{{#pmid:28684471|PMID2868441}}. Past research had also suggested that neural crest derived adrenal gland cells migrate using the sympathetic ganglia to the adrenal gland or preaortic ganglion, following different pathways, to reach their specific destination. However the results have shown that the pathways used to reach its destinations overlapped. This would suggest that there is a possibility of the cells using the same pathway to move from the beginning production to the destination that is the adrenal medulla (for chromaffin cells) and the preaortic ganglion (other cells involved in the sympathetic system).

One particular study done by M.Yamato in 2004, along with his fellow scientists attempted to study the migration of neural crest cells in Wistar rats. In order to observe the formation adrenal medulla from the neural crest cells during the embryonic period, Yamato used anti - tyrosine hydroxylase (TH) antiserum injected into the rat embryos between 13-17 days of gestation. The anti - TH antiserum stain allows the scientists to visualize the neural crest cells under a light microscope. Later three dimensional images were created. From the images observed between 13 to 15 days of gestation, the TH - positive cells can be seen to move from the dorsal to the adrenal primordium{{#pmid:15240937|PMID15240937}}. After 16 days it was observed that a capsule had formed in some parts and TH - positive cells had penetrated the adrenal gland{{#pmid:15240937|PMID15240937}}. At seventeen days, TH - positive cells can be seen collecting at the medial part of the adrenal gland. The reconstructed images also shows that at the later stages during the 16-17 days of gestation, the accumulation of TH - positive cells grow and in combination with cell division leads to the formation of the adrenal medulla.

=====Chicken models=====
Chicken and rat models are often the most commonly used models when dealing with neural crest cells. In this particular review, collates multiple researchers results and presents evidence to discuss previous information suggesting that sympathetic neurons and chromaffin cells do not share a common progenitor{{#pmid:3693940|PMID3693940}}. The relevant study involved the use of cell cultures, Sympathoadrneal (SA) progenitor cells from embryonic(from chick embryos) and eary developmental stages were able to be procured. From these cultures it was easy to identify that glucocorticoids were crucial in the differentiation of SA cells into their derivatives, sympathetic neurons and chromaffin cells.

[[File:Expression of BMP protein 4 .jpg|300px|thumb|right|Expression of BMP - 4 in the adrenal cortex at developmental stages. Shows the movement of the chromaffin progenitors moving from each stage of development. A-D: collection of progenitors outside E-H: cells have begun to penetrate the adrenal cortical region I-L: chromaffin cells have completely intergrated intergreted within the gland sg: sympathetic ganglia ac:adrenal cortical region ag: adrenal gland da: dorsal aortic region]]

Another study conducted deals with the role of the bone morphogenetic protein(BMP-4) and its importance in the development of the adrenal medullary cells, chromaffin cells{{#pmid:18945349|PMID18945349}}. Previous research had shown that BMP - 4 a growth factor is plays an important role in the regulation of chromaffin cell production{{#pmid:10679774|PMID10679774}}. The researchers incubated chick embryos for 3 - 9 embryonic days and dissected them to be used for tissue cultures. Embryonic day 8 chick embryos had BMP - 4 overexpressing cells implanted in the sympathetic ganglia area, as well as other neurons which contained chromaffin like cells. What was observed was an increase in size and numbers of 'chromaffin' granules{{#pmid:18945349|PMID18945349}}. As a result it was concluded that although BMP - 4 promotes certain chromaffin traits, it does not have the capability to convert sympathetic neurons into a chromaffin type cell.

===Current research (labs)===
----

==== Generation of Adrenal Chromaffin-like Cells from Human Pluripotent Stem Cells====

As explained above the adrenal medulla plays an important part in the autonomic system of an adult human. The chromaffin cells, in particular, are important neural crest derived cell that is closely related to the adrenal medulla. Previous findings have focused specifically on the mechanisms controlling the NCC migration and how these cells go on to form the different derivatives in their particular destinations in the embryo. For example, as previously explained studies have shown that chromaffin cells have been observed to move to the adrenal gland to form the medulla of the adrenal gland. This report goes through a recent study that involves the adrenal medullary cells, in particular chromaffin cells, and their potential to be used to model certain pathological diseases related to these cells. This is part of a study that also involves neural crest cells and their ability to differentiate into multiple different types of cells<ref>Lumb, R., & Schwarz, Q. (2015). Sympathoadrenal neural crest cells: The known, unknown and forgotten?. Development, Growth & Differentiation, 57(2), 146-157. doi: 10.1111/dgd.12189</ref>. Neural crest cells and SAPs from human embryonic cells and induced pluripotent stem cells were generated to be used in the experiment. By exposing the pluripotent stem cells to BMP4 in vitro, results showed that these cells would 'upregulate' the chromaffin cell - specific marker PMNT (an enzyme that synthesizes adrenaline). Furthermore when the cells from human embryos were implanted into avian embryos, there was a visible potential for the human cells to differentiate into cells that expressed the chromaffin cell markers{{#pmid:5768882|PMID5768882}}.

====Multipotent Peripheral Glial Cells Generate Neuroendocrine Cells of the Adrenal Medulla====

Similar to the first study, this one also focuses on the chromaffin cells and their relationship to the adrenal medulla. Chromaffin cells often represent the main endocrine component that is believed to differentiate from neural crest cells{{#pmid:28684471|PMID28684471}}. The study focuses specifically on the idea that previous research has suggested that nerve - associated schwann cell precursor is a progenitor of chromaffin cells. What the findings suggested was that peripheral nerves provided migration routes for the progenitors. This is backed up by the results, a high concentration of chromaffin cells can be found being derived from the nerve, as nerve ablated mice in the experiment showed a large difference of 78% less cells compared to the control. Other than this, the study also brought to light the proliferative potential of the cells from nerves, with different other cell types being discovered as well (including cells such as parasympathetic{{#pmid:24925912|PMID24925912}} and melanocytes {{#pmid:19837037 |PMID19837037}}). The findings would provide useful information into further understanding the adrenal gland and its embryonic origins (as there is still much to learn regarding the formation of the adrenal medulla) but also pathological diseases such as neuroblastoma and pheochromatocytoma which are most common in the adrenal glandular region {{#pmid:23106811|PMID23106811}}.

===Glossary===
----
*BMP4 - Bone Morphogenic Protein 4
*DOPA - Dihydroxyphenylalanine
*GATA3 - Transcription factor 3 for GATA gene
*GN - Ganglioneuroma
*GRN - Gene Regulatory Network
*HNK1 - Human Natural Killer 1
*HVA - Homovanillic Acid
*L-DOPA - L-3,4-dihydroxyphenylalanine
*PAX - Paired Box
*PCC - Pheochromocytoma
*PGL - Pheochromocytoma Paraganglioma
*SGC - Small Granule Containing cells
*SOX - Sry Box
*TH - Tyrosine Hydroxylase
*VMA -Vanilmandelic Acid

===Reference list===

2018 Group Project 1

2018-10-16T01:31:51Z

Z5113627: /* Abnormalities/abnormal development */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===

----

The neural crest of an embryo migrates and differentiates to form various components of the body. This transient population of pluripotent stem-cells give rise to many complex and different structures across the adult by chemical signalling. One of these tissues is the medulla of the adrenal gland which is involved in the production of epinephrine and norepinephrine. This project will comprehensively outline the history of neural crest research, the embryonic developmental time course, tissue and organ structure, molecular mechanisms, abnormalities, animal models and current research.

===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
[[File:NC Location.jpg|right|450px|thumb|The neural crest]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb|465px]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniably lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Embryonic origins===
----
[[File:Trunk_NCC_migration.jpg|left|450px|thumb|Trunk NCC migration]]
The adrenal gland is made up of the adrenal cortex and adrenal medulla, which both have different embryonic origins. The adrenal medulla arises from the neural crest tissue, found near the level of the coeliac plexus & sympathetic ganglion at somites 18-24 {{#pmid:16124976|PMID16124976}}. Specifically, this neural crest tissue comes from the trunk neural crest cells (see above figure to determine the approximate location in an embryo) <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
The trunk neural crest coordinates the development of the endocrine system, secretory cells, the peripheral nervous system and, to some degree, skeletal development, as well as innervation of the intestine {{#pmid: 28287247|PMID 28287247}}. The trunk neural cells arise caudally, undergo an epithelial to mesenchymal transition and follow three migratory pathways {{#pmid:20399766|PMID20399766}}.
[[File:Differentiation_of_NCC.jpg|left|580px|thumb|Differentiation of chromaffin cells]]
- A dorsolateral pathway (between ectoderm and somites), these become melanocytes, travel up to the point of the dermis and become a major part of the hair follicles and skin <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
- A ventrolateral pathway (through the somites)
- A ventromedial pathway (between neural tube and posterior schlerotome){{#pmid:20399766|PMID20399766}}.

Migration of neural crest cells from the sympathetic ganglion is what leads to the development of the adrenal medulla. In week 8 of development, immature cells called neuroblasts migrate through to the inner portion of the medulla, where they become the adrenal medulla {{#pmid:19683477|PMID19683477}}. Chromaffin cells are neuroendocrine cells and are found in the sympathetic ganglia and make up the majority of the adrenal medulla{{#pmid:19683477|PMID19683477}}. They synthesise and release a range of hormones in the body and arise from the temporary neural crest. The term chromaffin was inspired by the staining capacity of these cells when they came into contact with chrome salts. They make, store, export and use catecholamines, responsible for making noradrenaline and originate at the caudal region of somites 18-24 of the neural crest, also known as the adrenomedullary region {{#pmid:19683477|PMID19683477}}.

For cells to leave the neural crest and begin their migration, certain conditions need to be met, that is, the cells need to be loosely connected, their tight junctions becoming relaxed, initiated by "Slug protein" and a loss of N-Cadherin which also leads to the loosening of these junctions. The surrounding matrix as well as chemotactic and stem cell factors of the neural tube are then what dictates how the neural crest cells move, some proteins stopping their migration to that area and others encouraging the movement <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. After splitting apart, the first neural crest cells move ventrally and pass into the spaces between the somites and then, through the anterior portions of each segment until they arrive at the para-aortic sites, where they become the cells of the sympathetic ganglia and the adrenal medulla {{#pmid:19683477|PMID19683477}}. BMP-4 (bone morphogenetic protein 4) then acts on these neural crest cells, preventing them from becoming cells that have a neural function and causing them to become chromaffin cells at the adrenal medulla. Glucocorticoids then play a role in maintenance of chromaffin cells in postnatal life, this was only found recently, as previously it was thought that glucocorticoids were responsible entirely for the differentiation of neural crest cells into chromaffin, or adrenomedullary cells {{#pmid:23220335|PMID23220335}}.

===Anatomy and Functions===

----

====Anatomy and Histology====

The adrenal medulla makes up the inner section of the adrenal glands, and is surrounded by the cortex, and a connective tissue capsule. It lies in the centre of the gland and it rarely measures no more than 2mm in thickness {{#pmid:21107679|PMID21107679}}. The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The adrenal medulla contains secretory cells called chromaffin cells due to the agents they produce when oxidised, such as chromate {{#pmid:11215683|PMID11215683}}. These cells secrete epinephrine, norepinephrine, chromogranin and neuropeptides in response to various substances such as acetylcholine <ref name="PMID11215683"/>. [[File:ADRENAL MEDULLA .jpg|600px|thumb|right|Adrenal Medulla Histology]]

There are many types of highly differentiated cells in the adult adrenal medulla:
- Epinephrine cells (90% of all chromaffin cells) {{#pmid:24715564|PMID24715564}}
- Norepinephrine cells (10% of all chromaffin cells) <ref name="PMID24715564"/>
- Small granule-containing cells (SGCs) <ref name="PMID11215683"/>

These cells also synthesise, store and secrete catecholamines through controlled and regulated pathways <ref name="PMID24715564"/>, such as various peptides like substance P and neurotensin.These cells have unique neuroendocrine characteristics as a result of their neural-crest origin. They receive preganglionic innervation by thoracic splanchnic nerves, and could almost be considered a specialised sympathetic ganglion. With postganglgionic bodies, cells of the medulla are densely clustered around their vasculature for the secretion of hormones into the bloodstream to moderate the concentration of epinephrine and norepinephrine. The adrenal medulla also contains presynaptic sympathetic ganglion cells <ref name="PMID11215683"/>. The small granule-containing cells are usually found in clusters whereas, the ganglion cells are found either individually or in clusters, usually dispersed among the chromaffin cells or among the nerve fibres {{#pmid:18021328|PMID18021328}}. During embryonic development (around weeks 9-12), in contrast to the developing adrenal cortex, the medulla does not show evidence of an organised structure other than a small cluster of cells scattered throughout its cortex {{#pmid:30247985|PMID30247985}}.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus. {{#pmid:11215683|PMID11215683}}

[[File:Dd.jpg|400px|thumb|right|Adult Adrenal Glands in situ]]
----
====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses. {{#pmid:19396395|PMID19396395}}

'''Adult Function'''

While the adrenal cortex releases glucocorticoids in response to long term stress, the adrenal medulla releases its hormones in response to short-term, acute stress. The adrenal medulla contains the neuroendocrine chromaffin cells which are responsible for secreting adrenaline and noradrenaline. The function of these hormones is primarily to maintain the body’s homeostasis, especially of the internal organs, and to properly activate the autonomic stress response, more commonly known as the ‘fight or flight’ response {{#pmid:30237243|PMID30237243}}. Thus the function of the medulla includes signalling the liver and skeletal muscles to convert glycogen into glucose for increased energy. This results in increased blood glucose levels. These hormones also increase the heart rate, pulse and blood pressure in preparation for the fight or flight response. In addition to this, these hormones dilate the lung airways and prompt vasodilation to further increase oxygenation of important organs such as the lung, brain and heart. Vasoconstriction of blood vessels is also prompted to other less essential organs such as the bladder and the digestive system.

Other effects also include pupil dilation, dry mouth and a loss in peripheral vision <ref name="PMID18021328"/>. Paramount to the correct response of chromaffin cells is the synaptic connection of the preganglionic cells which originate from the central nervous system and project axons into the adrenal medulla. While this is a very important relationship, the mechanisms of this remains unknown <ref name="PMID30237243"/>. In addition to the release of catecholamines, cells in the medulla also release peptides through the process of exocytosis from chromaffin granules, to help regulate blood pressure and regulation throughout the body. These peptides also regulate the release of adrenaline and noradrenaline, blood vessel contraction and the immune response <ref name="PMID18021328"/>.

'''Embryonic function'''

The current knowledge about the development of the adrenal gland is limited, with nearly all models being from animals, and very limited functional data available from human fetal adrenals <ref name="PMID30247985"/>. Thus for these reasons, there is scarce information available on the embryonic adrenal medullary functions. Nevertheless, there is accumulating evidence that the catecholamines in the fetal adrenal medulla plays an important role in the time of delivery by controlling thermogenesis and heart regulation {{#pmid:6998630|PMID6998630}}.

The hormones released by the medulla during birth also play a key role for the newborn’s adaptation to extrauterine life. Despite the immaturity of the adrenal medulla at birth, it is known that respiratory, metabolic and cardiovascular changes during delivery are dependent on the adrenomedullary hormones {{#pmid:3280659|PMID3280659}}. Experimental data from human and animal fetal research shows that the fetal sympathoadrenal system, consisting of the adrenal medulla, sympathetic neurons and chromaffin tissue work together to maintain fetal homeostasis {{#pmid:6346884|PMID6346884}}. The adrenal medulla thus appears to provide vital physiological functions for fetal and neonatal survival, especially during birth.

----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

The 'story' of the Adrenal Medulla's neural crest tissue begins at the process of neurulation, the formation of the neural tube from the folding neural plate, which is comprised of developing ectoderm which is opposite to the primitive streak. It is here that several key chemical players are at work. The classic interpretation of Sonic Hedgehog (Shh) and Wnt signalling pathways as the only mediators here, has been shown to be incorrect. Research has uncovered other signallers such as:

*Bone-Morphogenic-Protein-4 (BMP4) for the regional expression of nervous system distinctions in the growing neural plate. This maintains two important embryonic trancription factors known as Paired-Box (PAX) Genes 3 and 7 which can allow for expression of neural crest markers HNK-1, SRY-Box (SOX) 8, 9 and 10 as the neural tube closes and the neural crest delaminates from the folding. {{#pmid:16688176|PMID16688176}}

*Slug via Wnt signalling, this allows for the loosening of gap junctions in the extracellular matrix surrounding the newly-formed neural tube and trunk of the embryo. This extracellular matrix has chemo-attractant molecules

[[File:Catecholamine_Synthesis.jpg|400px|thumb|right|Biochemical Cascade of Catecholamine Synthesis]]

The importance of Somitogenesis and Neural Crest come to a head when neural crest cells must migrate anteriorly past somites 18 to 24

Members of the SOX gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands. {{#pmid:18272785|PMID18272785}}

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well. {{#pmid:19396395|PMID19396395}}

===Abnormalities/abnormal development===
----

Abnormalities of the Adrenal Medulla are much less common than its mesoderm-derived shell of the Adrenal Gland. Three of the most notorious abnormalities of the Adrenal Medulla include:

* Pheochromocytomas
* Ganglioneuromas
* Neuroblastomas

Pheochromocytomas (PCCs) are variable neoplasias of the adrenal medulla's chromaffin cells. There are many classifications of PCCs, with autosomal-dominant germ-line mutations and heredities being one of the main causes. Familial pheochromocytoma-paraganglioma (PGL) syndromes exist, with PGL1 having mutations of the SDHD gene, PGL3 being mutated of the SDHC gene and PGL4 having mutation of the SDHB gene. These phenotypically present as extra-adrenal chromaffin bodies, malformation of the adrenal glands themselves, absence of chromaffin bodies and fluctuations in circulating catecholamines. {{#pmid:18021328|PMID18021328}}

Ganglioneuromas (GNs) are classically-benign growths that are very rare and arise from neural crest tissue. They are not circumscribed to the adrenal medulla, but also are found in the sympathetic chain and trunk ganglia. As a result of their scarcity, not much is known about them other than a few aberrant genes and generic clinical presentations. ERBB3, the receptor tyrosine kinas is understood to be important in the development of GNs, as well as an extremely high prevalence of up-regulated GATA3. A key thing to note is also the '''lack''' of N-MYC expression in GNs, which is quite prominent in neuroblastomas and other neoplasias. {{#pmid:29085827|PMID29085827}} {{#pmid:23715162|PMID23715162}}

Neuroblastomas (NBs) are a more aggressive form of cancer, derived from neuroblasts - the precursor cells to neurons. A rather common pediatric cancer, they are often in children who are in risk factor groups such as those with aforementioned familial cancer syndromes, neurofibromatosis-1. These tumours often present with extremely variable catecholamine concentrations, which has implications for blood pressure, heart contractility and much more. Urinary excretion of norepinephrine, homovanillic acid (HVA) and vanilmandelic acid (VMA) can be used to help diagnose a suspected lesion of the adrenal gland, as these chemicals are associated with altered chemical cascades that are suspicious of neuroblastic change. {{#pmid:16372223|PMID16372223}}

Apart from these abnormalities, there are other pathologies that may be connected to the adrenal medulla. One such example is a pathology of the Organ of Zuckerkandl. Also known as the para-aortic body, the Organ of Zuckerkandl is a primarily-gestational organ comprised of chromaffin cells and serves a similar purpose to the adrenal medulla in neonatal life.

===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

====Chromaffin cells====
There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells{{#pmid:19377845|PMID19377845}}. The neural crest cells give rise to chromaffin cells of the adrenal medulla.

=====Rat Models=====
[[File:Adrenal gland.png|300px|thumb|right|3D images showing TH - positive cells accumulating at the cranial and audal ends of the adrenal gland. A. A observation of adrenal gland and surrounding structures (at 17 days of gestation). B. Enhanced image to further focus on the dark TH - positive cells. C. Image with the other structures removed.]]
Previous research has reported that nueral crest cells differentiate into chromaffin cells around 19 days of gestation before forming the adrenal medulla{{#pmid:28684471|PMID2868441}}. Past research had also suggested that neural crest derived adrenal gland cells migrate using the sympathetic ganglia to the adrenal gland or preaortic ganglion, following different pathways, to reach their specific destination. However the results have shown that the pathways used to reach its destinations overlapped. This would suggest that there is a possibility of the cells using the same pathway to move from the beginning production to the destination that is the adrenal medulla (for chromaffin cells) and the preaortic ganglion (other cells involved in the sympathetic system).

One particular study done by M.Yamato in 2004, along with his fellow scientists attempted to study the migration of neural crest cells in Wistar rats. In order to observe the formation adrenal medulla from the neural crest cells during the embryonic period, Yamato used anti - tyrosine hydroxylase (TH) antiserum injected into the rat embryos between 13-17 days of gestation. The anti - TH antiserum stain allows the scientists to visualize the neural crest cells under a light microscope. Later three dimensional images were created. From the images observed between 13 to 15 days of gestation, the TH - positive cells can be seen to move from the dorsal to the adrenal primordium{{#pmid:15240937|PMID15240937}}. After 16 days it was observed that a capsule had formed in some parts and TH - positive cells had penetrated the adrenal gland{{#pmid:15240937|PMID15240937}}. At seventeen days, TH - positive cells can be seen collecting at the medial part of the adrenal gland. The reconstructed images also shows that at the later stages during the 16-17 days of gestation, the accumulation of TH - positive cells grow and in combination with cell division leads to the formation of the adrenal medulla.

=====Chicken models=====
Chicken and rat models are often the most commonly used models when dealing with neural crest cells. In this particular review, collates multiple researchers results and presents evidence to discuss previous information suggesting that sympathetic neurons and chromaffin cells do not share a common progenitor{{#pmid:3693940|PMID3693940}}. The relevant study involved the use of cell cultures, Sympathoadrneal (SA) progenitor cells from embryonic(from chick embryos) and eary developmental stages were able to be procured. From these cultures it was easy to identify that glucocorticoids were crucial in the differentiation of SA cells into their derivatives, sympathetic neurons and chromaffin cells.

[[File:Expression of BMP protein 4 .jpg|300px|thumb|right|Expression of BMP - 4 in the adrenal cortex at developmental stages. Shows the movement of the chromaffin progenitors moving from each stage of development. A-D: collection of progenitors outside E-H: cells have begun to penetrate the adrenal cortical region I-L: chromaffin cells have completely intergrated intergreted within the gland sg: sympathetic ganglia ac:adrenal cortical region ag: adrenal gland da: dorsal aortic region]]

Another study conducted deals with the role of the bone morphogenetic protein(BMP-4) and its importance in the development of the adrenal medullary cells, chromaffin cells{{#pmid:18945349|PMID18945349}}. Previous research had shown that BMP - 4 a growth factor is plays an important role in the regulation of chromaffin cell production{{#pmid:10679774|PMID10679774}}. The researchers incubated chick embryos for 3 - 9 embryonic days and dissected them to be used for tissue cultures. Embryonic day 8 chick embryos had BMP - 4 overexpressing cells implanted in the sympathetic ganglia area, as well as other neurons which contained chromaffin like cells. What was observed was an increase in size and numbers of 'chromaffin' granules{{#pmid:18945349|PMID18945349}}. As a result it was concluded that although BMP - 4 promotes certain chromaffin traits, it does not have the capability to convert sympathetic neurons into a chromaffin type cell.

===Current research (labs)===
----

==== Generation of Adrenal Chromaffin-like Cells from Human Pluripotent Stem Cells====

As explained above the adrenal medulla plays an important part in the autonomic system of an adult human. The chromaffin cells, in particular, are important neural crest derived cell that is closely related to the adrenal medulla. Previous findings have focused specifically on the mechanisms controlling the NCC migration and how these cells go on to form the different derivatives in their particular destinations in the embryo. For example, as previously explained studies have shown that chromaffin cells have been observed to move to the adrenal gland to form the medulla of the adrenal gland. This report goes through a recent study that involves the adrenal medullary cells, in particular chromaffin cells, and their potential to be used to model certain pathological diseases related to these cells. This is part of a study that also involves neural crest cells and their ability to differentiate into multiple different types of cells<ref>Lumb, R., & Schwarz, Q. (2015). Sympathoadrenal neural crest cells: The known, unknown and forgotten?. Development, Growth & Differentiation, 57(2), 146-157. doi: 10.1111/dgd.12189</ref>. Neural crest cells and SAPs from human embryonic cells and induced pluripotent stem cells were generated to be used in the experiment. By exposing the pluripotent stem cells to BMP4 in vitro, results showed that these cells would 'upregulate' the chromaffin cell - specific marker PMNT (an enzyme that synthesizes adrenaline). Furthermore when the cells from human embryos were implanted into avian embryos, there was a visible potential for the human cells to differentiate into cells that expressed the chromaffin cell markers{{#pmid:5768882|PMID5768882}}.

====Multipotent Peripheral Glial Cells Generate Neuroendocrine Cells of the Adrenal Medulla====

Similar to the first study, this one also focuses on the chromaffin cells and their relationship to the adrenal medulla. Chromaffin cells often represent the main endocrine component that is believed to differentiate from neural crest cells{{#pmid:28684471|PMID28684471}}. The study focuses specifically on the idea that previous research has suggested that nerve - associated schwann cell precursor is a progenitor of chromaffin cells. What the findings suggested was that peripheral nerves provided migration routes for the progenitors. This is backed up by the results, a high concentration of chromaffin cells can be found being derived from the nerve, as nerve ablated mice in the experiment showed a large difference of 78% less cells compared to the control. Other than this, the study also brought to light the proliferative potential of the cells from nerves, with different other cell types being discovered as well (including cells such as parasympathetic{{#pmid:24925912|PMID24925912}} and melanocytes {{#pmid:19837037 |PMID19837037}}). The findings would provide useful information into further understanding the adrenal gland and its embryonic origins (as there is still much to learn regarding the formation of the adrenal medulla) but also pathological diseases such as neuroblastoma and pheochromatocytoma which are most common in the adrenal glandular region {{#pmid:23106811|PMID23106811}}.

===Glossary===
----
===Reference list===

2018 Group Project 1

2018-10-15T12:51:00Z

Z5113627: /* Abnormalities/abnormal development */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===

----

The neural crest of an embryo differentiates and migrates to form various components of the body. This transient population of pluripotent stem-cells give rise to many complex and different structures across the adult by chemical signalling. One of these tissues is the medulla of the adrenal gland which is involved in the production of epinephrine and norepinephrine. This project will comprehensively outline the history of neural crest research, the embryonic developmental time course, tissue and organ structure, molecular mechanisms, abnormalities, animal models and current research.

===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.
[[File:NC Location.jpg|left|450px|thumb|The neural crest]]

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniably lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Embryonic origins===
----
[[File:Trunk_NCC_migration.jpg|left|450px|thumb|Trunk NCC migration]]
The adrenal gland is made up of the adrenal cortex and adrenal medulla, which both have different embryonic origins. The adrenal medulla arises from the neural crest tissue, found near the level of the coeliac plexus & sympathetic ganglion at somites 18-24 {{#pmid:16124976|PMID16124976}}. Specifically, this neural crest tissue comes from the trunk neural crest cells (see above figure to determine the approximate location in an embryo) <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
The trunk neural crest coordinates the development of the endocrine system, secretory cells, the peripheral nervous system and, to some degree, skeletal development, as well as innervation of the intestine {{#pmid: 28287247|PMID 28287247}}. The trunk neural cells arise caudally, undergo an epithelial to mesenchymal transition and follow three migratory pathways {{#pmid:20399766|PMID20399766}}.
[[File:Differentiation_of_NCC.jpg|left|580px|thumb|Differentiation of chromaffin cells]]
- A dorsolateral pathway (between ectoderm and somites), these become melanocytes, travel up to the point of the dermis and become a major part of the hair follicles and skin <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
- A ventrolateral pathway (through the somites)
- A ventromedial pathway (between neural tube and posterior schlerotome){{#pmid:20399766|PMID20399766}}.

Migration of neural crest cells from the sympathetic ganglion is what leads to the development of the adrenal medulla. In week 8 of development, immature cells called neuroblasts migrate through to the inner portion of the medulla, where they become the adrenal medulla {{#pmid:19683477|PMID19683477}}. Chromaffin cells are neuroendocrine cells and are found in the sympathetic ganglia and make up the majority of the adrenal medulla{{#pmid:19683477|PMID19683477}}. They synthesise and release a range of hormones in the body and arise from the temporary neural crest. The term chromaffin was inspired by the staining capacity of these cells when they came into contact with chrome salts. They make, store, export and use catecholamines, responsible for making noradrenaline and originate at the caudal region of somites 18-24 of the neural crest, also known as the adrenomedullary region {{#pmid:19683477|PMID19683477}}.

For cells to leave the neural crest and begin their migration, certain conditions need to be met, that is, the cells need to be loosely connected, their tight junctions becoming relaxed, initiated by "Slug protein" and a loss of N-Cadherin which also leads to the loosening of these junctions. The surrounding matrix as well as chemotactic and stem cell factors of the neural tube are then what dictates how the neural crest cells move, some proteins stopping their migration to that area and others encouraging the movement <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. After splitting apart, the first neural crest cells move ventrally and pass into the spaces between the somites and then, through the anterior portions of each segment until they arrive at the para-aortic sites, where they become the cells of the sympathetic ganglia and the adrenal medulla {{#pmid:19683477|PMID19683477}}. BMP-4 (bone morphogenetic protein 4) then acts on these neural crest cells, preventing them from becoming cells that have a neural function and causing them to become chromaffin cells at the adrenal medulla. Glucocorticoids then play a role in maintenance of chromaffin cells in postnatal life, this was only found recently, as previously it was thought that glucocorticoids were responsible entirely for the differentiation of neural crest cells into chromaffin, or adrenomedullary cells {{#pmid:23220335|PMID23220335}}.

===Anatomy and Functions===

====Anatomy and Histology====

The adrenal medulla makes up the inner section of the adrenal glands, and is surrounded by the cortex, and a connective tissue capsule. It lies in the centre of the gland and it rarely measures no more than 2mm in thickness {{#pmid:21107679|PMID21107679}}. The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The adrenal medulla contains secretory cells called chromaffin cells due to the agents they produce when oxidised, such as chromate {{#pmid:11215683|PMID11215683}}. These cells secrete epinephrine, norepinephrine, chromogranin and neuropeptides in response to various substances such as acetylcholine <ref name="PMID11215683"/>. [[File:ADRENAL MEDULLA .jpg|600px|thumb|right|Adrenal Medulla Histology]]

There are many types of highly differentiated cells in the adult adrenal medulla:
- Epinephrine cells (90% of all chromaffin cells) {{#pmid:24715564|PMID24715564}}
- Norepinephrine cells (10% of all chromaffin cells) <ref name="PMID24715564"/>
- Small granule-containing cells (SGCs) <ref name="PMID11215683"/>

These cells also synthesise, store and secrete catecholamines through controlled and regulated pathways <ref name="PMID24715564"/>, such as various peptides like substance P and neurotensin.These cells have unique neuroendocrine characteristics as a result of their neural-crest origin. They receive preganglionic innervation by thoracic splanchnic nerves, and could almost be considered a specialised sympathetic ganglion. With postganglgionic bodies, cells of the medulla are densely clustered around their vasculature for the secretion of hormones into the bloodstream to moderate the concentration of epinephrine and norepinephrine. The adrenal medulla also contains presynaptic sympathetic ganglion cells <ref name="PMID11215683"/>. The small granule-containing cells are usually found in clusters whereas, the ganglion cells are found either individually or in clusters, usually dispersed among the chromaffin cells or among the nerve fibres {{#pmid:18021328|PMID18021328}}. During embryonic development (around weeks 9-12), in contrast to the developing adrenal cortex, the medulla does not show evidence of an organised structure other than a small cluster of cells scattered throughout its cortex {{#pmid:30247985|PMID30247985}}.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus. {{#pmid:11215683|PMID11215683}}

[[File:Dd.jpg|400px|thumb|right|Adult Adrenal Glands in situ]]
----
====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses. {{#pmid:19396395|PMID19396395}}

'''Adult Function'''

While the adrenal cortex releases glucocorticoids in response to long term stress, the adrenal medulla releases its hormones in response to short-term, acute stress. The adrenal medulla contains the neuroendocrine chromaffin cells which are responsible for secreting adrenaline and noradrenaline. The function of these hormones is primarily to maintain the body’s homeostasis, especially of the internal organs, and to properly activate the autonomic stress response, more commonly known as the ‘fight or flight’ response {{#pmid:30237243|PMID30237243}}. Thus the function of the medulla includes signalling the liver and skeletal muscles to convert glycogen into glucose for increased energy. This results in increased blood glucose levels. These hormones also increase the heart rate, pulse and blood pressure in preparation for the fight or flight response. In addition to this, these hormones dilate the lung airways and prompt vasodilation to further increase oxygenation of important organs such as the lung, brain and heart. Vasoconstriction of blood vessels is also prompted to other less essential organs such as the bladder and the digestive system.

Other effects also include pupil dilation, dry mouth and a loss in peripheral vision <ref name="PMID18021328"/>. Paramount to the correct response of chromaffin cells is the synaptic connection of the preganglionic cells which originate from the central nervous system and project axons into the adrenal medulla. While this is a very important relationship, the mechanisms of this remains unknown <ref name="PMID30237243"/>. In addition to the release of catecholamines, cells in the medulla also release peptides through the process of exocytosis from chromaffin granules, to help regulate blood pressure and regulation throughout the body. These peptides also regulate the release of adrenaline and noradrenaline, blood vessel contraction and the immune response <ref name="PMID18021328"/>.

'''Embryonic function'''

The current knowledge about the development of the adrenal gland is limited, with nearly all models being from animals, and very limited functional data available from human fetal adrenals <ref name="PMID30247985"/>. Thus for these reasons, there is scarce information available on the embryonic adrenal medullary functions. Nevertheless, there is accumulating evidence that the catecholamines in the fetal adrenal medulla plays an important role in the time of delivery by controlling thermogenesis and heart regulation {{#pmid:6998630|PMID6998630}}.

The hormones released by the medulla during birth also play a key role for the newborn’s adaptation to extrauterine life. Despite the immaturity of the adrenal medulla at birth, it is known that respiratory, metabolic and cardiovascular changes during delivery are dependent on the adrenomedullary hormones {{#pmid:3280659|PMID3280659}}. Experimental data from human and animal fetal research shows that the fetal sympathoadrenal system, consisting of the adrenal medulla, sympathetic neurons and chromaffin tissue work together to maintain fetal homeostasis {{#pmid:6346884|PMID6346884}}. The adrenal medulla thus appears to provide vital physiological functions for fetal and neonatal survival, especially during birth.

----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

The 'story' of the Adrenal Medulla's neural crest tissue begins at the process of neurulation, the formation of the neural tube from the folding neural plate, which is comprised of developing ectoderm which is opposite to the primitive streak. It is here that several key chemical players are at work. The classic interpretation of Sonic Hedgehog (Shh) and Wnt signalling pathways as the only mediators here, has been shown to be incorrect. Research has uncovered other signallers such as:

*Bone-Morphogenic-Protein-4 (BMP4) for the regional expression of nervous system distinctions in the growing neural plate. This maintains two important embryonic trancription factors known as Paired-Box (PAX) Genes 3 and 7 which can allow for expression of neural crest markers HNK-1, SRY-Box (SOX) 8, 9 and 10 as the neural tube closes and the neural crest delaminates from the folding. {{#pmid:16688176|PMID16688176}}

*Slug via Wnt signalling, this allows for the loosening of gap junctions in the extracellular matrix surrounding the newly-formed neural tube and trunk of the embryo. This extracellular matrix has chemo-attractant molecules

[[File:Catecholamine_Synthesis.jpg|400px|thumb|right|Biochemical Cascade of Catecholamine Synthesis]]

The importance of Somitogenesis and Neural Crest come to a head when neural crest cells must migrate anteriorly past somites 18 to 24

Members of the SOX gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands. {{#pmid:18272785|PMID18272785}}

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well. {{#pmid:19396395|PMID19396395}}

===Abnormalities/abnormal development===
----

Abnormalities of the Adrenal Medulla are much less common than its mesoderm-derived shell of the Adrenal Gland. Three of the most notorious abnormalities of the Adrenal Medulla include:

* Pheochromocytomas
* Ganglioneuromas
* Neuroblastomas

Pheochromocytomas (PCCs) are variable neoplasias of the adrenal medulla's chromaffin cells. There are many classifications of PCCs, with autosomal-dominant germ-line mutations and heredities being one of the main causes. Familial phaeochromocytoma-paraganglioma (PGL) syndromes exist, with PGL1 having mutations of the SDHD gene, PGL3 being mutated of the SDHC gene and PGL4 having mutation of the SDHB gene. These phenotypically present as extra-adrenal chromaffin bodies, malformation of the adrenal glands themselves, absence of chromaffin bodies and fluctuations in circulating catecholamines. {{#pmid:18021328|PMID18021328}}

Ganglioneuromas (GNs) are classically-benign growths that are very rare and arise from neural crest tissue. They are not circumscribed to the adrenal medulla, but also are found in the sympathetic chain and trunk ganglia. As a result of their scarcity, not much is known about them other than a few aberrant genes and generic clinical presentations. ERBB3, the receptor tyrosine kinas is understood to be important in the development of GNs, as well as an extremely high prevalence of up-regulated GATA3. A key thing to note is also the '''lack''' of N-MYC expression in GNs, which is quite prominent in neuroblastomas and other neoplasias. {{#pmid:29085827|PMID29085827}} {{#pmid:23715162|PMID23715162}}

Neuroblastomas (NBs) are a more aggressive form of cancer, derived from neuroblasts - the precursor cells to neurons. A rather common pediatric cancer, they are often in children who are in risk factor groups such as those with aforementioned familial cancer syndromes, neurofibromatosis-1. These tumours often present with extremely variable catecholamine concentrations, which has implications for blood pressure, heart contractility and much more. Urinary excretion of norepinephrine, homovanillic acid (HVA) and vanilmandelic acid (VMA) can be used to help diagnose a suspected lesion of the adrenal gland, as these chemicals are associated with altered chemical cascades that are suspicious of neuroblastic change. {{#pmid:16372223|PMID16372223}}

Apart from these abnormalities, there are other pathologies that may be connected to the adrenal medulla. One such example is a pathology of the Organ of Zuckerkandl. Also known as the para-aortic body, the Organ of Zuckerkandl is a primarily-gestational organ comprised of chromaffin cells and serves a similar purpose to the adrenal medulla in neonatal life.

===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

====Chromaffin cells====
There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells{{#pmid:19377845|PMID19377845}}. The neural crest cells give rise to chromaffin cells of the adrenal medulla.

=====Rat Models=====
[[File:Adrenal gland.png|300px|thumb|right|3D images showing TH - positive cells accumulating at the cranial and audal ends of the adrenal gland. A. A observation of adrenal gland and surrounding structures (at 17 days of gestation). B. Enhanced image to further focus on the dark TH - positive cells. C. Image with the other structures removed.]]
Previous research has reported that nueral crest cells differentiate into chromaffin cells around 19 days of gestation before forming the adrenal medulla{{#pmid:28684471|PMID2868441}}. Past research had also suggested that neural crest derived adrenal gland cells migrate using the sympathetic ganglia to the adrenal gland or preaortic ganglion, following different pathways, to reach their specific destination. However the results have shown that the pathways used to reach its destinations overlapped. This would suggest that there is a possibility of the cells using the same pathway to move from the beginning production to the destination that is the adrenal medulla (for chromaffin cells) and the preaortic ganglion (other cells involved in the sympathetic system).

One particular study done by M.Yamato in 2004, along with his fellow scientists attempted to study the migration of neural crest cells in Wistar rats. In order to observe the formation adrenal medulla from the neural crest cells during the embryonic period, Yamato used anti - tyrosine hydroxylase (TH) antiserum injected into the rat embryos between 13-17 days of gestation. The anti - TH antiserum stain allows the scientists to visualize the neural crest cells under a light microscope. Later three dimensional images were created. From the images observed between 13 to 15 days of gestation, the TH - positive cells can be seen to move from the dorsal to the adrenal primordium{{#pmid:15240937|PMID15240937}}. After 16 days it was observed that a capsule had formed in some parts and TH - positive cells had penetrated the adrenal gland{{#pmid:15240937|PMID15240937}}. At seventeen days, TH - positive cells can be seen collecting at the medial part of the adrenal gland. The reconstructed images also shows that at the later stages during the 16-17 days of gestation, the accumulation of TH - positive cells grow and in combination with cell division leads to the formation of the adrenal medulla.

=====Chicken models=====
Chicken and rat models are often the most commonly used models when dealing with neural crest cells. In this particular review, collates multiple researchers results and presents evidence to discuss previous information suggesting that sympathetic neurons and chromaffin cells do not share a common progenitor{{#pmid:3693940|PMID3693940}}. The relevant study involved the use of cell cultures, Sympathoadrneal (SA) progenitor cells from embryonic(from chick embryos) and eary developmental stages were able to be procured. From these cultures it was easy to identify that glucocorticoids were crucial in the differentiation of SA cells into their derivatives, sympathetic neurons and chromaffin cells.

[[File:Expression of BMP protein 4 .jpg|300px|thumb|right|Expression of BMP - 4 in the adrenal cortex at developmental stages. Shows the movement of the chromaffin progenitors moving from each stage of development. A-D: collection of progenitors outside E-H: cells have begun to penetrate the adrenal cortical region I-L: chromaffin cells have completely intergrated intergreted within the gland sg: sympathetic ganglia ac:adrenal cortical region ag: adrenal gland da: dorsal aortic region]]

Another study conducted deals with the role of the bone morphogenetic protein(BMP-4) and its importance in the development of the adrenal medullary cells, chromaffin cells{{#pmid:18945349|PMID18945349}}. Previous research had shown that BMP - 4 a growth factor is plays an important role in the regulation of chromaffin cell production{{#pmid:10679774|PMID10679774}}. The researchers incubated chick embryos for 3 - 9 embryonic days and dissected them to be used for tissue cultures. Embryonic day 8 chick embryos had BMP - 4 overexpressing cells implanted in the sympathetic ganglia area, as well as other neurons which contained chromaffin like cells. What was observed was an increase in size and numbers of 'chromaffin' granules{{#pmid:18945349|PMID18945349}}. As a result it was concluded that although BMP - 4 promotes certain chromaffin traits, it does not have the capability to convert sympathetic neurons into a chromaffin type cell.

===Current research (labs)===
----

==== Generation of Adrenal Chromaffin-like Cells from Human Pluripotent Stem Cells====

As explained above the adrenal medulla plays an important part in the autonomic system of an adult human. The chromaffin cells, in particular, are important neural crest derived cell that is closely related to the adrenal medulla. Previous findings have focused specifically on the mechanisms controlling the NCC migration and how these cells go on to form the different derivatives in their particular destinations in the embryo. For example, as previously explained studies have shown that chromaffin cells have been observed to move to the adrenal gland to form the medulla of the adrenal gland. This report goes through a recent study that involves the adrenal medullary cells, in particular chromaffin cells, and their potential to be used to model certain pathological diseases related to these cells. This is part of a study that also involves neural crest cells and their ability to differentiate into multiple different types of cells<ref>Lumb, R., & Schwarz, Q. (2015). Sympathoadrenal neural crest cells: The known, unknown and forgotten?. Development, Growth & Differentiation, 57(2), 146-157. doi: 10.1111/dgd.12189</ref>. Neural crest cells and SAPs from human embryonic cells and induced pluripotent stem cells were generated to be used in the experiment. By exposing the pluripotent stem cells to BMP4 in vitro, results showed that these cells would 'upregulate' the chromaffin cell - specific marker PMNT (an enzyme that synthesizes adrenaline). Furthermore when the cells from human embryos were implanted into avian embryos, there was a visible potential for the human cells to differentiate into cells that expressed the chromaffin cell markers{{#pmid:5768882|PMID5768882}}.

====Multipotent Peripheral Glial Cells Generate Neuroendocrine Cells of the Adrenal Medulla====

Similar to the first study, this one also focuses on the chromaffin cells and their relationship to the adrenal medulla. Chromaffin cells often represent the main endocrine component that is believed to differentiate from neural crest cells{{#pmid:28684471|PMID28684471}}. The study focuses specifically on the idea that previous research has suggested that nerve - associated schwann cell precursor is a progenitor of chromaffin cells. What the findings suggested was that peripheral nerves provided migration routes for the progenitors. This is backed up by the results, a high concentration of chromaffin cells can be found being derived from the nerve, as nerve ablated mice in the experiment showed a large difference of 78% less cells compared to the control. Other than this, the study also brought to light the proliferative potential of the cells from nerves, with different other cell types being discovered as well (including cells such as parasympathetic{{#pmid:24925912|PMID24925912}} and melanocytes {{#pmid:19837037 |PMID19837037}}). The findings would provide useful information into further understanding the adrenal gland and its embryonic origins (as there is still much to learn regarding the formation of the adrenal medulla) but also pathological diseases such as neuroblastoma and pheochromatocytoma which are most common in the adrenal glandular region {{#pmid:23106811|PMID23106811}}.

===Glossary===
----
===Reference list===

2018 Group Project 1

2018-10-15T12:16:28Z

Z5113627: /* Abnormalities/abnormal development */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===

----

The neural crest of an embryo differentiates and migrates to form various components of the body. This transient population of pluripotent stem-cells give rise to many complex and different structures across the adult by chemical signalling. One of these tissues is the medulla of the adrenal gland which is involved in the production of epinephrine and norepinephrine. This project will comprehensively outline the history of neural crest research, the embryonic developmental time course, tissue and organ structure, molecular mechanisms, abnormalities, animal models and current research.

===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.
[[File:NC Location.jpg|left|450px|thumb|The neural crest]]

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniably lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Embryonic origins===
----
[[File:Trunk_NCC_migration.jpg|left|450px|thumb|Trunk NCC migration]]
The adrenal gland is made up of the adrenal cortex and adrenal medulla, which both have different embryonic origins. The adrenal medulla arises from the neural crest tissue, found near the level of the coeliac plexus & sympathetic ganglion at somites 18-24 {{#pmid:16124976|PMID16124976}}. Specifically, this neural crest tissue comes from the trunk neural crest cells (see above figure to determine the approximate location in an embryo) <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
The trunk neural crest coordinates the development of the endocrine system, secretory cells, the peripheral nervous system and, to some degree, skeletal development, as well as innervation of the intestine {{#pmid: 28287247|PMID 28287247}}. The trunk neural cells arise caudally, undergo an epithelial to mesenchymal transition and follow three migratory pathways {{#pmid:20399766|PMID20399766}}.
[[File:Differentiation_of_NCC.jpg|left|580px|thumb|Differentiation of chromaffin cells]]
- A dorsolateral pathway (between ectoderm and somites), these become melanocytes, travel up to the point of the dermis and become a major part of the hair follicles and skin <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
- A ventrolateral pathway (through the somites)
- A ventromedial pathway (between neural tube and posterior schlerotome){{#pmid:20399766|PMID20399766}}.

Migration of neural crest cells from the sympathetic ganglion is what leads to the development of the adrenal medulla. In week 8 of development, immature cells called neuroblasts migrate through to the inner portion of the medulla, where they become the adrenal medulla {{#pmid:19683477|PMID19683477}}. Chromaffin cells are neuroendocrine cells and are found in the sympathetic ganglia and make up the majority of the adrenal medulla{{#pmid:19683477|PMID19683477}}. They synthesise and release a range of hormones in the body and arise from the temporary neural crest. The term chromaffin was inspired by the staining capacity of these cells when they came into contact with chrome salts. They make, store, export and use catecholamines, responsible for making noradrenaline and originate at the caudal region of somites 18-24 of the neural crest, also known as the adrenomedullary region {{#pmid:19683477|PMID19683477}}.

For cells to leave the neural crest and begin their migration, certain conditions need to be met, that is, the cells need to be loosely connected, their tight junctions becoming relaxed, initiated by "Slug protein" and a loss of N-Cadherin which also leads to the loosening of these junctions. The surrounding matrix as well as chemotactic and stem cell factors of the neural tube are then what dictates how the neural crest cells move, some proteins stopping their migration to that area and others encouraging the movement <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. After splitting apart, the first neural crest cells move ventrally and pass into the spaces between the somites and then, through the anterior portions of each segment until they arrive at the para-aortic sites, where they become the cells of the sympathetic ganglia and the adrenal medulla {{#pmid:19683477|PMID19683477}}. BMP-4 (bone morphogenetic protein 4) then acts on these neural crest cells, preventing them from becoming cells that have a neural function and causing them to become chromaffin cells at the adrenal medulla. Glucocorticoids then play a role in maintenance of chromaffin cells in postnatal life, this was only found recently, as previously it was thought that glucocorticoids were responsible entirely for the differentiation of neural crest cells into chromaffin, or adrenomedullary cells {{#pmid:23220335|PMID23220335}}.

===Anatomy and Functions===

====Anatomy and Histology====

The adrenal medulla makes up the inner section of the adrenal glands, and is surrounded by the cortex, and a connective tissue capsule. It lies in the centre of the gland and it rarely measures no more than 2mm in thickness {{#pmid:21107679|PMID21107679}}. The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The adrenal medulla contains secretory cells called chromaffin cells due to the agents they produce when oxidised, such as chromate {{#pmid:11215683|PMID11215683}}. These cells secrete epinephrine, norepinephrine, chromogranin and neuropeptides in response to various substances such as acetylcholine <ref name="PMID11215683"/>. [[File:ADRENAL MEDULLA .jpg|600px|thumb|right|Adrenal Medulla Histology]]

There are many types of highly differentiated cells in the adult adrenal medulla:
- Epinephrine cells (90% of all chromaffin cells) {{#pmid:24715564|PMID24715564}}
- Norepinephrine cells (10% of all chromaffin cells) <ref name="PMID24715564"/>
- Small granule-containing cells (SGCs) <ref name="PMID11215683"/>

These cells also synthesise, store and secrete catecholamines through controlled and regulated pathways <ref name="PMID24715564"/>, such as various peptides like substance P and neurotensin.These cells have unique neuroendocrine characteristics as a result of their neural-crest origin. They receive preganglionic innervation by thoracic splanchnic nerves, and could almost be considered a specialised sympathetic ganglion. With postganglgionic bodies, cells of the medulla are densely clustered around their vasculature for the secretion of hormones into the bloodstream to moderate the concentration of epinephrine and norepinephrine. The adrenal medulla also contains presynaptic sympathetic ganglion cells <ref name="PMID11215683"/>. The small granule-containing cells are usually found in clusters whereas, the ganglion cells are found either individually or in clusters, usually dispersed among the chromaffin cells or among the nerve fibres {{#pmid:18021328|PMID18021328}}. During embryonic development (around weeks 9-12), in contrast to the developing adrenal cortex, the medulla does not show evidence of an organised structure other than a small cluster of cells scattered throughout its cortex {{#pmid:30247985|PMID30247985}}.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus. {{#pmid:11215683|PMID11215683}}

[[File:Dd.jpg|400px|thumb|right|Adult Adrenal Glands in situ]]
----
====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses. {{#pmid:19396395|PMID19396395}}

'''Adult Function'''

While the adrenal cortex releases glucocorticoids in response to long term stress, the adrenal medulla releases its hormones in response to short-term, acute stress. The adrenal medulla contains the neuroendocrine chromaffin cells which are responsible for secreting adrenaline and noradrenaline. The function of these hormones is primarily to maintain the body’s homeostasis, especially of the internal organs, and to properly activate the autonomic stress response, more commonly known as the ‘fight or flight’ response {{#pmid:30237243|PMID30237243}}. Thus the function of the medulla includes signalling the liver and skeletal muscles to convert glycogen into glucose for increased energy. This results in increased blood glucose levels. These hormones also increase the heart rate, pulse and blood pressure in preparation for the fight or flight response. In addition to this, these hormones dilate the lung airways and prompt vasodilation to further increase oxygenation of important organs such as the lung, brain and heart. Vasoconstriction of blood vessels is also prompted to other less essential organs such as the bladder and the digestive system.

Other effects also include pupil dilation, dry mouth and a loss in peripheral vision <ref name="PMID18021328"/>. Paramount to the correct response of chromaffin cells is the synaptic connection of the preganglionic cells which originate from the central nervous system and project axons into the adrenal medulla. While this is a very important relationship, the mechanisms of this remains unknown <ref name="PMID30237243"/>. In addition to the release of catecholamines, cells in the medulla also release peptides through the process of exocytosis from chromaffin granules, to help regulate blood pressure and regulation throughout the body. These peptides also regulate the release of adrenaline and noradrenaline, blood vessel contraction and the immune response <ref name="PMID18021328"/>.

'''Embryonic function'''

The current knowledge about the development of the adrenal gland is limited, with nearly all models being from animals, and very limited functional data available from human fetal adrenals <ref name="PMID30247985"/>. Thus for these reasons, there is scarce information available on the embryonic adrenal medullary functions. Nevertheless, there is accumulating evidence that the catecholamines in the fetal adrenal medulla plays an important role in the time of delivery by controlling thermogenesis and heart regulation {{#pmid:6998630|PMID6998630}}.

The hormones released by the medulla during birth also play a key role for the newborn’s adaptation to extrauterine life. Despite the immaturity of the adrenal medulla at birth, it is known that respiratory, metabolic and cardiovascular changes during delivery are dependent on the adrenomedullary hormones {{#pmid:3280659|PMID3280659}}. Experimental data from human and animal fetal research shows that the fetal sympathoadrenal system, consisting of the adrenal medulla, sympathetic neurons and chromaffin tissue work together to maintain fetal homeostasis {{#pmid:6346884|PMID6346884}}. The adrenal medulla thus appears to provide vital physiological functions for fetal and neonatal survival, especially during birth.

----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

The 'story' of the Adrenal Medulla's neural crest tissue begins at the process of neurulation, the formation of the neural tube from the folding neural plate, which is comprised of developing ectoderm which is opposite to the primitive streak. It is here that several key chemical players are at work. The classic interpretation of Sonic Hedgehog (Shh) and Wnt signalling pathways as the only mediators here, has been shown to be incorrect. Research has uncovered other signallers such as:

*Bone-Morphogenic-Protein-4 (BMP4) for the regional expression of nervous system distinctions in the growing neural plate. This maintains two important embryonic trancription factors known as Paired-Box (PAX) Genes 3 and 7 which can allow for expression of neural crest markers HNK-1, SRY-Box (SOX) 8, 9 and 10 as the neural tube closes and the neural crest delaminates from the folding. {{#pmid:16688176|PMID16688176}}

*Slug via Wnt signalling, this allows for the loosening of gap junctions in the extracellular matrix surrounding the newly-formed neural tube and trunk of the embryo. This extracellular matrix has chemo-attractant molecules

[[File:Catecholamine_Synthesis.jpg|400px|thumb|right|Biochemical Cascade of Catecholamine Synthesis]]

The importance of Somitogenesis and Neural Crest come to a head when neural crest cells must migrate anteriorly past somites 18 to 24

Members of the SOX gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands. {{#pmid:18272785|PMID18272785}}

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well. {{#pmid:19396395|PMID19396395}}

===Abnormalities/abnormal development===
----

Abnormalities of the Adrenal Medulla are much less common than its mesoderm-derived shell of the Adrenal Gland. Three of the most notorious abnormalities of the Adrenal Medulla include:

* Pheochromocytomas
* Ganglioneuromas
* Neuroblastomas

Pheochromocytomas (PCCs) are variable neoplasias of the adrenal medulla's chromaffin cells. There are many classifications of PCCs, with autosomal-dominant germ-line mutations and heredities being one of the main causes. Familial phaeochromocytoma-paraganglioma (PGL) syndromes exist, with PGL1 having mutations of the SDHD gene, PGL3 being mutated of the SDHC gene and PGL4 having mutation of the SDHB gene. These phenotypically present as extra-adrenal chromaffin bodies, malformation of the adrenal glands themselves, absence of chromaffin bodies and fluctuations in circulating catecholamines. {{#pmid:18021328|PMID18021328}}

Ganglioneuromas (GNs) Are classically-benign growths that are very rare and arise from neural crest tissue. They are not circumscribed to the adrenal medulla, but also are found in the sympathetic chain and trunk ganglia. As a result of their scarcity, not much is known about them other than a few aberrant genes and generic clinical presentations. ERBB3, the receptor tyrosine kinas is understood to be important in the development of GNs, as well as an extremely high prevalence of up-regulated GATA3. A key thing to note is also the '''lack''' of N-MYC expression in GNs, which is quite prominent in neuroblastomas and other neoplasias. {{#pmid:29085827|PMID29085827}}

Neuroblastomas-

Apart from these abnormalities, there are other pathologies that may be connected to the adrenal medulla. One such example is a pathology of the Organ of Zuckerkandl. Also known as the para-aortic body, the Organ of Zuckerkandl is a primarily-gestational organ comprised of chromaffin cells and serves a similar purpose to the adrenal medulla in neonatal life.

===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

====Chromaffin cells====
There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells{{#pmid:19377845|PMID19377845}}. The neural crest cells give rise to chromaffin cells of the adrenal medulla.

=====Rat Models=====
[[File:Adrenal gland.png|300px|thumb|right|3D images showing TH - positive cells accumulating at the cranial and audal ends of the adrenal gland. A. A observation of adrenal gland and surrounding structures (at 17 days of gestation). B. Enhanced image to further focus on the dark TH - positive cells. C. Image with the other structures removed.]]
Previous research has reported that nueral crest cells differentiate into chromaffin cells around 19 days of gestation before forming the adrenal medulla{{#pmid:28684471|PMID2868441}}. Past research had also suggested that neural crest derived adrenal gland cells migrate using the sympathetic ganglia to the adrenal gland or preaortic ganglion, following different pathways, to reach their specific destination. However the results have shown that the pathways used to reach its destinations overlapped. This would suggest that there is a possibility of the cells using the same pathway to move from the beginning production to the destination that is the adrenal medulla (for chromaffin cells) and the preaortic ganglion (other cells involved in the sympathetic system).

One particular study done by M.Yamato in 2004, along with his fellow scientists attempted to study the migration of neural crest cells in Wistar rats. In order to observe the formation adrenal medulla from the neural crest cells during the embryonic period, Yamato used anti - tyrosine hydroxylase (TH) antiserum injected into the rat embryos between 13-17 days of gestation. The anti - TH antiserum stain allows the scientists to visualize the neural crest cells under a light microscope. Later three dimensional images were created. From the images observed between 13 to 15 days of gestation, the TH - positive cells can be seen to move from the dorsal to the adrenal primordium{{#pmid:15240937|PMID15240937}}. After 16 days it was observed that a capsule had formed in some parts and TH - positive cells had penetrated the adrenal gland{{#pmid:15240937|PMID15240937}}. At seventeen days, TH - positive cells can be seen collecting at the medial part of the adrenal gland. The reconstructed images also shows that at the later stages during the 16-17 days of gestation, the accumulation of TH - positive cells grow and in combination with cell division leads to the formation of the adrenal medulla.

=====Chicken models=====
Chicken and rat models are often the most commonly used models when dealing with neural crest cells. In this particular review, collates multiple researchers results and presents evidence to discuss previous information suggesting that sympathetic neurons and chromaffin cells do not share a common progenitor{{#pmid:3693940|PMID3693940}}. The relevant study involved the use of cell cultures, Sympathoadrneal (SA) progenitor cells from embryonic(from chick embryos) and eary developmental stages were able to be procured. From these cultures it was easy to identify that glucocorticoids were crucial in the differentiation of SA cells into their derivatives, sympathetic neurons and chromaffin cells.

[[File:Expression of BMP protein 4 .jpg|300px|thumb|right|Expression of BMP - 4 in the adrenal cortex at developmental stages. Shows the movement of the chromaffin progenitors moving from each stage of development. A-D: collection of progenitors outside E-H: cells have begun to penetrate the adrenal cortical region I-L: chromaffin cells have completely intergrated intergreted within the gland sg: sympathetic ganglia ac:adrenal cortical region ag: adrenal gland da: dorsal aortic region]]

Another study conducted deals with the role of the bone morphogenetic protein(BMP-4) and its importance in the development of the adrenal medullary cells, chromaffin cells{{#pmid:18945349|PMID18945349}}. Previous research had shown that BMP - 4 a growth factor is plays an important role in the regulation of chromaffin cell production{{#pmid:10679774|PMID10679774}}. The researchers incubated chick embryos for 3 - 9 embryonic days and dissected them to be used for tissue cultures. Embryonic day 8 chick embryos had BMP - 4 overexpressing cells implanted in the sympathetic ganglia area, as well as other neurons which contained chromaffin like cells. What was observed was an increase in size and numbers of 'chromaffin' granules{{#pmid:18945349|PMID18945349}}. As a result it was concluded that although BMP - 4 promotes certain chromaffin traits, it does not have the capability to convert sympathetic neurons into a chromaffin type cell.

===Current research (labs)===
----

==== Generation of Adrenal Chromaffin-like Cells from Human Pluripotent Stem Cells====

As explained above the adrenal medulla plays an important part in the autonomic system of an adult human. The chromaffin cells, in particular, are important neural crest derived cell that is closely related to the adrenal medulla. Previous findings have focused specifically on the mechanisms controlling the NCC migration and how these cells go on to form the different derivatives in their particular destinations in the embryo. For example, as previously explained studies have shown that chromaffin cells have been observed to move to the adrenal gland to form the medulla of the adrenal gland. This report goes through a recent study that involves the adrenal medullary cells, in particular chromaffin cells, and their potential to be used to model certain pathological diseases related to these cells. This is part of a study that also involves neural crest cells and their ability to differentiate into multiple different types of cells<ref>Lumb, R., & Schwarz, Q. (2015). Sympathoadrenal neural crest cells: The known, unknown and forgotten?. Development, Growth & Differentiation, 57(2), 146-157. doi: 10.1111/dgd.12189</ref>. Neural crest cells and SAPs from human embryonic cells and induced pluripotent stem cells were generated to be used in the experiment. By exposing the pluripotent stem cells to BMP4 in vitro, results showed that these cells would 'upregulate' the chromaffin cell - specific marker PMNT (an enzyme that synthesizes adrenaline). Furthermore when the cells from human embryos were implanted into avian embryos, there was a visible potential for the human cells to differentiate into cells that expressed the chromaffin cell markers{{#pmid:5768882|PMID5768882}}.

====Multipotent Peripheral Glial Cells Generate Neuroendocrine Cells of the Adrenal Medulla====

Similar to the first study, this one also focuses on the chromaffin cells and their relationship to the adrenal medulla. Chromaffin cells often represent the main endocrine component that is believed to differentiate from neural crest cells{{#pmid:28684471|PMID28684471}}. The study focuses specifically on the idea that previous research has suggested that nerve - associated schwann cell precursor is a progenitor of chromaffin cells. What the findings suggested was that peripheral nerves provided migration routes for the progenitors. This is backed up by the results, a high concentration of chromaffin cells can be found being derived from the nerve, as nerve ablated mice in the experiment showed a large difference of 78% less cells compared to the control. Other than this, the study also brought to light the proliferative potential of the cells from nerves, with different other cell types being discovered as well (including cells such as parasympathetic{{#pmid:24925912|PMID24925912}} and melanocytes {{#pmid:19837037 |PMID19837037}}). The findings would provide useful information into further understanding the adrenal gland and its embryonic origins (as there is still much to learn regarding the formation of the adrenal medulla) but also pathological diseases such as neuroblastoma and pheochromatocytoma which are most common in the adrenal glandular region {{#pmid:23106811|PMID23106811}}.

===Glossary===
----
===Reference list===

2018 Group Project 1

2018-10-15T08:45:55Z

Z5113627: /* Abnormalities/abnormal development */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===

----

The neural crest of an embryo differentiates and migrates to form various components of the body. This transient population of pluripotent stem-cells give rise to many complex and different structures across the adult by chemical signalling. One of these tissues is the medulla of the adrenal gland which is involved in the production of epinephrine and norepinephrine. This project will comprehensively outline the history of neural crest research, the embryonic developmental time course, tissue and organ structure, molecular mechanisms, abnormalities, animal models and current research.

===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.
[[File:NC Location.jpg|left|450px|thumb|The neural crest]]

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniably lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Embryonic origins===
----
[[File:Trunk_NCC_migration.jpg|left|450px|thumb|Trunk NCC migration]]
The adrenal gland is made up of the adrenal cortex and adrenal medulla, which both have different embryonic origins. The adrenal medulla arises from the neural crest tissue, found near the level of the coeliac plexus & sympathetic ganglion at somites 18-24 {{#pmid:16124976|PMID16124976}}. Specifically, this neural crest tissue comes from the trunk neural crest cells (see above figure to determine the approximate location in an embryo) <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
The trunk neural crest coordinates the development of the endocrine system, secretory cells, the peripheral nervous system and, to some degree, skeletal development, as well as innervation of the intestine {{#pmid: 28287247|PMID 28287247}}. The trunk neural cells arise caudally, undergo an epithelial to mesenchymal transition and follow three migratory pathways {{#pmid:20399766|PMID20399766}}.
[[File:Differentiation_of_NCC.jpg|left|580px|thumb|Differentiation of chromaffin cells]]
- A dorsolateral pathway (between ectoderm and somites), these become melanocytes, travel up to the point of the dermis and become a major part of the hair follicles and skin <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
- A ventrolateral pathway (through the somites)
- A ventromedial pathway (between neural tube and posterior schlerotome){{#pmid:20399766|PMID20399766}}.

Migration of neural crest cells from the sympathetic ganglion is what leads to the development of the adrenal medulla. In week 8 of development, immature cells called neuroblasts migrate through to the inner portion of the medulla, where they become the adrenal medulla {{#pmid:19683477|PMID19683477}}. Chromaffin cells are neuroendocrine cells and are found in the sympathetic ganglia and make up the majority of the adrenal medulla{{#pmid:19683477|PMID19683477}}. They synthesise and release a range of hormones in the body and arise from the temporary neural crest. The term chromaffin was inspired by the staining capacity of these cells when they came into contact with chrome salts. They make, store, export and use catecholamines, responsible for making noradrenaline and originate at the caudal region of somites 18-24 of the neural crest, also known as the adrenomedullary region {{#pmid:19683477|PMID19683477}}.

For cells to leave the neural crest and begin their migration, certain conditions need to be met, that is, the cells need to be loosely connected, their tight junctions becoming relaxed, initiated by "Slug protein" and a loss of N-Cadherin which also leads to the loosening of these junctions. The surrounding matrix as well as chemotactic and stem cell factors of the neural tube are then what dictates how the neural crest cells move, some proteins stopping their migration to that area and others encouraging the movement <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. After splitting apart, the first neural crest cells move ventrally and pass into the spaces between the somites and then, through the anterior portions of each segment until they arrive at the para-aortic sites, where they become the cells of the sympathetic ganglia and the adrenal medulla {{#pmid:19683477|PMID19683477}}. BMP-4 (bone morphogenetic protein 4) then acts on these neural crest cells, preventing them from becoming cells that have a neural function and causing them to become chromaffin cells at the adrenal medulla. Glucocorticoids then play a role in maintenance of chromaffin cells in postnatal life, this was only found recently, as previously it was thought that glucocorticoids were responsible entirely for the differentiation of neural crest cells into chromaffin, or adrenomedullary cells {{#pmid:23220335|PMID23220335}}.

===Anatomy and Functions===

====Anatomy and Histology====

The adrenal medulla makes up the inner section of the adrenal glands, and is surrounded by the cortex, and a connective tissue capsule. It lies in the centre of the gland and it rarely measures no more than 2mm in thickness {{#pmid:21107679|PMID21107679}}. The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The adrenal medulla contains secretory cells called chromaffin cells due to the agents they produce when oxidised, such as chromate {{#pmid:11215683|PMID11215683}}. These cells secrete epinephrine, norepinephrine, chromogranin and neuropeptides in response to various substances such as acetylcholine <ref name="PMID11215683"/>.

There are many types of highly differentiated cells in the adult adrenal medulla:
- Epinephrine cells (90% of all chromaffin cells) {{#pmid:24715564|PMID24715564}}
- Norepinephrine cells (10% of all chromaffin cells) <ref name="PMID24715564"/>
- Small granule-containing cells (SGCs) <ref name="PMID11215683"/>

These cells also synthesise, store and secrete catecholamines through controlled and regulated pathways <ref name="PMID24715564"/>, such as various peptides like substance P and neurotensin.These cells have unique neuroendocrine characteristics as a result of their neural-crest origin. They receive preganglionic innervation by thoracic splanchnic nerves, and could almost be considered a specialised sympathetic ganglion. With postganglgionic bodies, cells of the medulla are densely clustered around their vasculature for the secretion of hormones into the bloodstream to moderate the concentration of epinephrine and norepinephrine. The adrenal medulla also contains presynaptic sympathetic ganglion cells <ref name="PMID11215683"/>. The small granule-containing cells are usually found in clusters whereas, the ganglion cells are found either individually or in clusters, usually dispersed among the chromaffin cells or among the nerve fibres {{#pmid:18021328|PMID18021328}}. During embryonic development (around weeks 9-12), in contrast to the developing adrenal cortex, the medulla does not show evidence of an organised structure other than a small cluster of cells scattered throughout its cortex {{#pmid:30247985|PMID30247985}}.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus. {{#pmid:11215683|PMID11215683}}

[[File:Dd.jpg|400px|thumb|right|Adult Adrenal Glands in situ]]
----
====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses. {{#pmid:19396395|PMID19396395}}

'''Adult Function'''
While the adrenal cortex releases glucocorticoids in response to long term stress, the adrenal medulla releases its hormones in response to short-term, acute stress. The adrenal medulla contains the neuroendocrine chromaffin cells which are responsible for secreting adrenaline and noradrenaline. The function of these hormones is primarily to maintain the body’s homeostasis, especially of the internal organs, and to properly activate the autonomic stress response, more commonly known as the ‘fight or flight’ response {{#pmid:30237243|PMID30237243}}. Thus the function of the medulla includes signalling the liver and skeletal muscles to convert glycogen into glucose for increased energy. This results in increased blood glucose levels. These hormones also increase the heart rate, pulse and blood pressure in preparation for the fight or flight response. In addition to this, these hormones dilate the lung airways and prompt vasodilation to further increase oxygenation of important organs such as the lung, brain and heart. Vasoconstriction of blood vessels is also prompted to other less essential organs such as the bladder and the digestive system.

Other effects also include pupil dilation, dry mouth and a loss in peripheral vision <ref name="PMID18021328"/>. Paramount to the correct response of chromaffin cells is the synaptic connection of the preganglionic cells which originate from the central nervous system and project axons into the adrenal medulla. While this is a very important relationship, the mechanisms of this remains unknown <ref name="PMID30237243"/>. In addition to the release of catecholamines, cells in the medulla also release peptides through the process of exocytosis from chromaffin granules, to help regulate blood pressure and regulation throughout the body. These peptides also regulate the release of adrenaline and noradrenaline, blood vessel contraction and the immune response <ref name="PMID18021328"/>.

'''Embryonic function'''
The current knowledge about the development of the adrenal gland is limited, with nearly all models being from animals, and very limited functional data available from human fetal adrenals <ref name="PMID30247985"/>. Thus for these reasons, there is scarce information available on the embryonic adrenal medullary functions. Nevertheless, there is accumulating evidence that the catecholamines in the fetal adrenal medulla plays an important role in the time of delivery by controlling thermogenesis and heart regulation {{#pmid:6998630|PMID6998630}}.

The hormones released by the medulla during birth also play a key role for the newborn’s adaptation to extrauterine life. Despite the immaturity of the adrenal medulla at birth, it is known that respiratory, metabolic and cardiovascular changes during delivery are dependent on the adrenomedullary hormones {{#pmid:3280659|PMID3280659}}. Experimental data from human and animal fetal research shows that the fetal sympathoadrenal system, consisting of the adrenal medulla, sympathetic neurons and chromaffin tissue work together to maintain fetal homeostasis {{#pmid:6346884|PMID6346884}}. The adrenal medulla thus appears to provide vital physiological functions for fetal and neonatal survival, especially during birth.

----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

The 'story' of the Adrenal Medulla's neural crest tissue begins at the process of neurulation, the formation of the neural tube from the folding neural plate, which is comprised of developing ectoderm which is opposite to the primitive streak. It is here that several key chemical players are at work. The classic interpretation of Sonic Hedgehog (Shh) and Wnt signalling pathways as the only mediators here, has been shown to be incorrect. Research has uncovered other signallers such as:

*Bone-Morphogenic-Protein-4 (BMP4) for the regional expression of nervous system distinctions in the growing neural plate. This maintains two important embryonic trancription factors known as Paired-Box (PAX) Genes 3 and 7 which can allow for expression of neural crest markers HNK-1, SRY-Box (SOX) 8, 9 and 10 as the neural tube closes and the neural crest delaminates from the folding. {{#pmid:16688176|PMID16688176}}

*Slug via Wnt signalling, this allows for the loosening of gap junctions in the extracellular matrix surrounding the newly-formed neural tube and trunk of the embryo. This extracellular matrix has chemo-attractant molecules

[[File:Catecholamine_Synthesis.jpg|400px|thumb|right|Biochemical Cascade of Catecholamine Synthesis]]

The importance of Somitogenesis and Neural Crest come to a head when neural crest cells must migrate anteriorly past somites 18 to 24

Members of the SOX gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands. {{#pmid:18272785|PMID18272785}}

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well. {{#pmid:19396395|PMID19396395}}

===Abnormalities/abnormal development===
----

Abnormalities of the Adrenal Medulla are much less common than its mesoderm-derived shell of the Adrenal Gland. Three of the most notorious abnormalities of the Adrenal Medulla include:

* Pheochromocytomas
* Ganglioneuromas
* Neuroblastomas

Pheochromocytomas (PCCs) are neoplasias of the adrenal medulla's chromaffin cells. There are many classifications of PCCs, with autosomal-dominant germ-line mutations and heredities being one of the main causes.

Ganglioneuromas-

Neuroblastomas-

Apart from these abnormalities, there are other pathologies that may be connected to the adrenal medulla. One such example is a pathology of the Organ of Zuckerkandl. Also known as the para-aortic body, the Organ of Zuckerkandl is a primarily-gestational organ comprised of chromaffin cells.

===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

====Chromaffin cells====
There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells{{#pmid:19377845|PMID19377845}}. The neural crest cells give rise to chromaffin cells of the adrenal medulla.

=====Rat Models=====
Previous research has reported that nueral crest cells differentiate into chromaffin cells around 19 days of gestation before forming the adrenal medulla{{#pmid:28684471|PMID2868441}}. Past research had also suggested that neural crest derived adrenal gland cells migrate using the sympathetic ganglia to the adrenal gland or preaortic ganglion, following different pathways, to reach their specific destination. However the results have shown that the pathways used to reach its destinations overlapped. This would suggest that there is a possibility of the cells using the same pathway to move from the beginning production to the destination that is the adrenal medulla (for chromaffin cells) and the preaortic ganglion (other cells involved in the sympathetic system).

One particular study done by M.Yamato in 2004, along with his fellow scientists attempted to study the migration of neural crest cells in Wistar rats. In order to observe the formation adrenal medulla from the neural crest cells during the embryonic period, Yamato used anti - tyrosine hydroxylase (TH) antiserum injected into the rat embryos between 13-17 days of gestation. The anti - TH antiserum stain allows the scientists to visualize the neural crest cells under a light microscope. Later three dimensional images were created. From the images observed between 13 to 15 days of gestation, the TH - positive cells can be seen to move from the dorsal to the adrenal primordium{{#pmid:15240937|PMID15240937}}. After 16 days it was observed that a capsule had formed in some parts and TH - positive cells had penetrated the adrenal gland{{#pmid:15240937|PMID15240937}}. At seventeen days, TH - positive cells can be seen collecting at the medial part of the adrenal gland. The reconstructed images also shows that at the later stages during the 16-17 days of gestation, the accumulation of TH - positive cells grow and in combination with cell division leads to the formation of the adrenal medulla.

(Pubmed: 15240937)

=====Chicken models=====
Chicken and rat models are often the most commonly used models when dealing with neural crest cells. In this particular review, collates multiple researchers results and presents evidence to discuss previous information suggesting that sympathetic neurons and chromaffin cells do not share a common progenitor{{#pmid:3693940|PMID3693940}}. The relevant study involved the use of cell cultures, Sympathoadrneal (SA) progenitor cells from embryonic(from chick embryos) and eary developmental stages were able to be procured. From these cultures it was easy to identify that glucocorticoids were crucial in the differentiation of SA cells into their derivatives, sympathetic neurons and chromaffin cells.

Another study conducted deals with the role of the bone morphogenetic protein(BMP-4) and its importance in the development of the adrenal medullary cells, chromaffin cells{{#pmid:18945349|PMID18945349}}. Previous research had shown that BMP - 4 a growth factor is plays an important role in the regulation of chromaffin cell production{{#pmid:10679774|PMID10679774}}. The researchers incubated chick embryos for 3 - 9 embryonic days and dissected them to be used for tissue cultures. Embryonic day 8 chick embryos had BMP - 4 overexpressing cells implanted in the sympathetic ganglia area, as well as other neurons which contained chromaffin like cells. What was observed was an increase in size and numbers of 'chromaffin' granules{{#pmid:18945349|PMID18945349}}. As a result it was concluded that although BMP - 4 promotes certain chromaffin traits, it does not have the capability to convert sympathetic neurons into a chromaffin type cell.

===Current research (labs)===
----

==== mulitpotent neural crest cells====

As explained above the adrenal medulla plays an important part in the autonomic system of an adult human. The chromaffin cells, in particular, are important neural crest derived cell that is closely related to the adrenal medulla. Previous findings have focused specifically on the mechanisms controlling the NCC migration and how these cells go on to form the different derivatives in their particular destinations in the embryo. For example, as previously explained studies have shown that chromaffin cells have been observed to move to the adrenal gland to form the medulla of the adrenal gland. This report goes through a recent study that involves the adrenal medullary cells, in particular chromaffin cells, and their potential to be used to model certain pathological diseases related to these cells. This is part of a study that also involves neural crest cells and their ability to differentiate into multiple different types of cells<ref>Lumb, R., & Schwarz, Q. (2015). Sympathoadrenal neural crest cells: The known, unknown and forgotten?. Development, Growth & Differentiation, 57(2), 146-157. doi: 10.1111/dgd.12189</ref>. Neural crest cells and SAPs from human embryonic cells
We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/dgd.12189

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693940/

===Glossary===
----
===Reference list===

2018 Group Project 1

2018-10-15T06:21:49Z

Z5113627: /* Introduction */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===

----

The neural crest of an embryo differentiates and migrates to form various components of the body. This transient population of pluripotent stem-cells give rise to many complex and different structures across the adult by chemical signalling. One of these tissues is the medulla of the adrenal gland which is involved in the production of epinephrine and norepinephrine. This project will comprehensively outline the history of neural crest research, the embryonic developmental time course, tissue and organ structure, molecular mechanisms, abnormalities, animal models and current research.

===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.
[[File:NC Location.jpg|left|450px|thumb|The neural crest]]

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniably lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Embryonic origins===
----
[[File:Trunk_NCC_migration.jpg|left|450px|thumb|Trunk NCC migration]]
The adrenal gland is made up of the adrenal cortex and adrenal medulla, which both have different embryonic origins. The adrenal medulla arises from the neural crest tissue, found near the level of the coeliac plexus & sympathetic ganglion at somites 18-24 {{#pmid:16124976|PMID16124976}}. Specifically, this neural crest tissue comes from the trunk neural crest cells (see above figure to determine the approximate location in an embryo) <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
The trunk neural crest coordinates the development of the endocrine system, secretory cells, the peripheral nervous system and, to some degree, skeletal development, as well as innervation of the intestine {{#pmid: 28287247|PMID 28287247}}. The trunk neural cells arise caudally, undergo an epithelial to mesenchymal transition and follow three migratory pathways {{#pmid:20399766|PMID20399766}}.
[[File:Differentiation_of_NCC.jpg|left|580px|thumb|Differentiation of chromaffin cells]]
- A dorsolateral pathway (between ectoderm and somites), these become melanocytes, travel up to the point of the dermis and become a major part of the hair follicles and skin <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
- A ventrolateral pathway (through the somites)
- A ventromedial pathway (between neural tube and posterior schlerotome){{#pmid:20399766|PMID20399766}}.

Migration of neural crest cells from the sympathetic ganglion is what leads to the development of the adrenal medulla. In week 8 of development, immature cells called neuroblasts migrate through to the inner portion of the medulla, where they become the adrenal medulla {{#pmid:19683477|PMID19683477}}. Chromaffin cells are neuroendocrine cells and are found in the sympathetic ganglia and make up the majority of the adrenal medulla{{#pmid:19683477|PMID19683477}}. They synthesise and release a range of hormones in the body and arise from the temporary neural crest. The term chromaffin was inspired by the staining capacity of these cells when they came into contact with chrome salts. They make, store, export and use catecholamines, responsible for making noradrenaline and originate at the caudal region of somites 18-24 of the neural crest, also known as the adrenomedullary region {{#pmid:19683477|PMID19683477}}.

For cells to leave the neural crest and begin their migration, certain conditions need to be met, that is, the cells need to be loosely connected, their tight junctions becoming relaxed, initiated by "Slug protein" and a loss of N-Cadherin which also leads to the loosening of these junctions. The surrounding matrix as well as chemotactic and stem cell factors of the neural tube are then what dictates how the neural crest cells move, some proteins stopping their migration to that area and others encouraging the movement <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. After splitting apart, the first neural crest cells move ventrally and pass into the spaces between the somites and then, through the anterior portions of each segment until they arrive at the para-aortic sites, where they become the cells of the sympathetic ganglia and the adrenal medulla {{#pmid:19683477|PMID19683477}}. BMP-4 (bone morphogenetic protein 4) then acts on these neural crest cells, preventing them from becoming cells that have a neural function and causing them to become chromaffin cells at the adrenal medulla. Glucocorticoids then play a role in maintenance of chromaffin cells in postnatal life, this was only found recently, as previously it was thought that glucocorticoids were responsible entirely for the differentiation of neural crest cells into chromaffin, or adrenomedullary cells {{#pmid:23220335|PMID23220335}}.

===Developmental/adult function===
----
====Normal Structure and Function of the Adrenal Medulla====

The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The medulla contains secretory cells, rich vasculature with a high surface area and presynaptic sympathetitic ganglion cells. These cells secrete epinephrine and norepinephrine in response to various substances such as acetylcholine.

There are multiple cell types of in the adult adrenal medulla:

* Chromaffin cells
* Epinephrine cells
* Norepinephrine cells
* Small granule-containing cells (SGCs)

These cells also produce various other peptides such as substance P and neurotensin. The adrenal medulla also contains presynaptic sympathetic ganglion cells. {{#pmid:1694230|PMID1694230}}

These cells have unique neuroendocrine characteristics as a result of their neural-crest origin. They receive preganglionic innervation by thoracic splanchnic nerves, and could almost be considered a specialised sympathetic ganglion. With postganglgionic bodies, cells of the medulla are densely clustered around their vasculature for the secretion of hormones into the bloodstream to moderate the concentration of epinephrine and norepinephrine.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus. {{#pmid:11215683|PMID11215683}} [[File:Dd.jpg|400px|thumb|right|Adult Adrenal Glands in situ]]

====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses. {{#pmid:19396395|PMID19396395}}

----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

The 'story' of the Adrenal Medulla's neural crest tissue begins at the process of neurulation, the formation of the neural tube from the folding neural plate, which is comprised of developing ectoderm which is opposite to the primitive streak. It is here that several key chemical players are at work. The classic interpretation of Sonic Hedgehog (Shh) and Wnt signalling pathways as the only mediators here, has been shown to be incorrect. Research has uncovered other signallers such as:

*Bone-Morphogenic-Protein-4 (BMP4) for the regional expression of nervous system distinctions in the growing neural plate. This maintains two important embryonic trancription factors known as Paired-Box (PAX) Genes 3 and 7 which can allow for expression of neural crest markers HNK-1, SRY-Box (SOX) 8, 9 and 10 as the neural tube closes and the neural crest delaminates from the folding. {{#pmid:16688176|PMID16688176}}

*Slug via Wnt signalling, this allows for the loosening of gap junctions in the extracellular matrix surrounding the newly-formed neural tube and trunk of the embryo. This extracellular matrix has chemo-attractant molecules

[[File:Catecholamine_Synthesis.jpg|400px|thumb|right|Biochemical Cascade of Catecholamine Synthesis]]

The importance of Somitogenesis and Neural Crest come to a head when neural crest cells must migrate anteriorly past somites 18 to 24

Members of the SOX gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands. {{#pmid:18272785|PMID18272785}}

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well. {{#pmid:19396395|PMID19396395}}

===Abnormalities/abnormal development===
----

Abnormalities of the Adrenal Medulla are much less common than its mesoderm-derived shell of the Adrenal Gland. Three of the most notorious abnormalities of the Adrenal Medulla include:

* Pheochromocytomas
* Ganglioneuromas
* Neuroblastomas

Pheochromocytomas-

Ganglioneuromas-

Neuroblastomas-

Apart from these abnormalities, there are other pathologies that may be connected to the adrenal medulla. One such example is a pathology of the Organ of Zuckerkandl. Also known as the para-aortic body, the Organ of Zuckerkandl is a primarily-gestational organ comprised of chromaffin cells.

===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

====Chromaffin cells====
There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells{{#pmid:19377845|PMID19377845}}. The neural crest cells give rise to chromaffin cells of the adrenal medulla.

=====Rat Models=====
Previous research has reported that nueral crest cells differentiate into chromaffin cells around 19 days of gestation before forming the adrenal medulla{{#pmid:28684471|PMID2868441}}. Past research had also suggested that neural crest derived adrenal gland cells migrate using the sympathetic ganglia to the adrenal gland or preaortic ganglion, following different pathways, to reach their specific destination. However the results have shown that the pathways used to reach its destinations overlapped. This would suggest that there is a possibility of the cells using the same pathway to move from the beginning production to the destination that is the adrenal medulla (for chromaffin cells) and the preaortic ganglion (other cells involved in the sympathetic system).

One particular study done by M.Yamato in 2004, along with his fellow scientists attempted to study the migration of neural crest cells in Wistar rats. In order to observe the formation adrenal medulla from the neural crest cells during the embryonic period, Yamato used anti - tyrosine hydroxylase (TH) antiserum injected into the rat embryos between 13-17 days of gestation. The anti - TH antiserum stain allows the scientists to visualize the neural crest cells under a light microscope. Later three dimensional images were created. From the images observed between 13 to 15 days of gestation, the TH - positive cells can be seen to move from the dorsal to the adrenal primordium{{#pmid:15240937|PMID15240937}}. After 16 days it was observed that a capsule had formed in some parts and TH - positive cells had penetrated the adrenal gland{{#pmid:15240937|PMID15240937}}. At seventeen days, TH - positive cells can be seen collecting at the medial part of the adrenal gland. The reconstructed images also shows that at the later stages during the 16-17 days of gestation, the accumulation of TH - positive cells grow and in combination with cell division leads to the formation of the adrenal medulla.

(Pubmed: 15240937)

=====Chicken models=====
Chicken and rat models are often the most commonly used models when dealing with neural crest cells. In this particular review, collates multiple researchers results and presents evidence to discuss previous information suggesting that sympathetic neurons and chromaffin cells do not share a common progenitor{{#pmid:3693940|PMID3693940}}. The relevant study involved the use of cell cultures, Sympathoadrneal (SA) progenitor cells from embryonic(from chick embryos) and eary developmental stages were able to be procured. From these cultures it was easy to identify that glucocorticoids were crucial in the differentiation of SA cells into their derivatives, sympathetic neurons and chromaffin cells.

Another study conducted deals with the role of the BMP-4 protein and its importance in the development of the adrenal medullary cells, chromaffin cells{{#pmid:18945349|PMID18945349}}. Previous research had shown that BMP - 4 a growth factor is plays an important role in the regulation of chromaffin cell production{{#pmid:10679774|PMID10679774}}. The researchers incubated chick embryos for 3 - 9 embryonic days and dissected them to be used for tissue cultures. From these

Cell culture studies using isolated SA progenitor cells from embryonic and early postnatal sympathetic ganglia and adrenal gland have suggested that glucocorticoids play a crucial role in the diversification of SA cells into sympathetic neurons and chromaffin cells [22-24]; for reviews see [2,5,6,25], by suppressing a neuronal differentiation programme in SA cells destined to become chromaffin cells. However, analysis of mice deficient for the glucocorticoid receptor [26] or lacking an adrenal cortex [27] revealed that chromaffin cell differentiation was largely unimpaired suggesting that cues unrelated to glucocorticoid receptor signalling and the adrenal cortex triggered the chromaffin phenotype. This notion was corroborated and extended by studies showing that chick SA progenitors are already heterogeneous in terms of neurofilament-M (NF-M) expression prior to populating the adrenal gland and sympathetic ganglia [28] with presumptive neuronal cells co-expressing tyrosine hydroxylase (TH) and NF-M, and presumptive neuroendocrine cells being TH-positive and NF-M-negative. This indicated that specification of the respective phenotypes occurred either during migration or even prior to migration at the level of the NT.

A recent study by Krispin et al. [7,29] showed that in the trunk NT of avian embryos, precursors for sympathetic ganglia, Schwann cells, sensory dorsal root ganglionic neurons, and melanocytes leave the NT in successive, largely non-overlapping waves, some being already distinct while still residing in the NT. Although adrenal chromaffin cells were not addressed in this study, the results raised the possibility that sympathetic neurons and chromaffin cells might also already be distinct at the level of the NT. We therefore conducted single cell electroporations (EPs) of green fluorescent protein (GFP)-DNA into pre-migratory NC cells at the level of somites 18–24 (“adrenomedullary level”), where both chromaffin cells and sympathetic neurons arise [30]. The timing and location of EPs was directed to label the earliest progenitors that undergo delamination, previously shown to generate the sympathetic lineage [7,29], and the progeny of labelled cells was then analysed at E6 following homing to their target areas. Our results indicate that in more than 80% of the cases the progeny of a single labelled cell ends up in both sympathetic ganglia and adrenal gland, being mostly NF-M-negative in the adrenal gland and NF-M-positive in sympathetic ganglia. This suggests that chromaffin cells and sympathetic neurons share a common progenitor in the NT and that diversification of the phenotypes occurs during migration or assembly in primary sympathetic ganglia at the dorsal aorta.
The sympathoadrenal (SA) cell lineage is a major sub-lineage of the NC that gives rise to sympathetic neurons, intra- and extra-adrenal chromaffin cells, and the small intensely fluorescent (SIF) cells, which are intermediate between sympathetic neurons and chromaffin cells [2-5]. SA derivatives share several features, including the ability to synthesize, store, and release catecholamines, but also exhibit traits specific for each cell type, such as axons, dendrites, and neurofilaments, which are only found in sympathetic neurons but not chromaffin cells.

3693940

Prenatal adrenal gland development has been described in numerous published reports covering a wide variety of species, including the ox (Katznelson, 1966; Wrobel and Suss, 1999), sheep (Davies, 1950; Wintour et al., 1975; Upadhyay and Zamboni, 1982; Naaman‐Reperant and Durand, 1997; Grino, 2004), swine (Sokolov et al., 2006) and mouse (Waring, 1935; Ikeda et al., 1994; Sass, 1996; Nyska and Maronpot, 1999; Bland et al., 2003; Val et al., 2007). Adrenal gland development also has been extensively described for humans as well (Kolliker, 1879; Minot, 1892; Zuckerkandl, 1912; Wieman, 1920; Ikeda et al., 1981; Langlois et al., 2002; Hanley and Arit, 2006).

https://www.sciencedirect.com/science/article/pii/S0925477302004550
http://dev.biologists.org/content/develop/126/13/2935.full.pdf

===Current research (labs)===
----

==== Sympathoadrenal neural crest cells====

As explained above the adrenal medulla plays an important part in the autonomic system of an adult human. The chromaffin cells, in particular, are important neural crest derived cell that is closely related to the adrenal medulla. Previous findings have focused specifically on the mechanisms controlling the NCC migration and how these cells go on to form the different derivatives in their particular destinations in the embryo. For example, as previously explained studies have shown that chromaffin cells have been observed to move to the adrenal gland to form the medulla of the adrenal gland.

The findings presented until now have focused on the mechanisms controlling migration along the dorsolateral path. In comparison, our understanding of the mechanisms controlling NCC migration along the ventral path are complicated by the fact that this population comprises multiple precursors that form different derivatives in distinct regions of the embryo. For example, ventrally migrating NCCs either stop within the sclerotome in close association with the neural tube to form neurons and glia of the sensory nervous system (i.e. the dorsal root ganglia [DRG]), while other NCCs continue to migrate further ventrally to form the autonomic nervous system (i.e. sympathetic ganglia and chromaffin cells of the adrenal gland)<ref>Lumb, R., & Schwarz, Q. (2015). Sympathoadrenal neural crest cells: The known, unknown and forgotten?. Development, Growth & Differentiation, 57(2), 146-157. doi: 10.1111/dgd.12189</ref>.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/dgd.12189

Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type.

The autonomic nervous system is very important in understanding the human body and in turn understanding health. This report goes through a recent study that involves the adrenal medullary cells, in particular chromaffin cells, and their potential to be used to model certain pathological diseases related to these cells. This is part of a study that also involves neural crest cells and their ability to differentiate into multiple different types of cells.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693940/

===Glossary===
----
===Reference list===

2018 Group Project 1

2018-10-15T06:16:33Z

Z5113627: /* Normal Structure and Function of the Adrenal Medulla */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===

----

The neural crest of an embryo differentiates and migrates to form various components of the body. One of these tissues is the medulla of the adrenal gland which is involved in the production of adrenalin and noradrenalin. This project will comprehensively outline the history of neural crest research, the embryonic developmental time course, tissue and organ structure, molecular mechanisms, abnormalities, animal models and current research.

===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.
[[File:NC Location.jpg|left|450px|thumb|The neural crest]]

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniably lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Embryonic origins===
----
[[File:Trunk_NCC_migration.jpg|left|450px|thumb|Trunk NCC migration]]
The adrenal gland is made up of the adrenal cortex and adrenal medulla, which both have different embryonic origins. The adrenal medulla arises from the neural crest tissue, found near the level of the coeliac plexus & sympathetic ganglion at somites 18-24 {{#pmid:16124976|PMID16124976}}. Specifically, this neural crest tissue comes from the trunk neural crest cells (see above figure to determine the approximate location in an embryo) <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
The trunk neural crest coordinates the development of the endocrine system, secretory cells, the peripheral nervous system and, to some degree, skeletal development, as well as innervation of the intestine {{#pmid: 28287247|PMID 28287247}}. The trunk neural cells arise caudally, undergo an epithelial to mesenchymal transition and follow three migratory pathways {{#pmid:20399766|PMID20399766}}.
[[File:Differentiation_of_NCC.jpg|left|580px|thumb|Differentiation of chromaffin cells]]
- A dorsolateral pathway (between ectoderm and somites), these become melanocytes, travel up to the point of the dermis and become a major part of the hair follicles and skin <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
- A ventrolateral pathway (through the somites)
- A ventromedial pathway (between neural tube and posterior schlerotome){{#pmid:20399766|PMID20399766}}.

Migration of neural crest cells from the sympathetic ganglion is what leads to the development of the adrenal medulla. In week 8 of development, immature cells called neuroblasts migrate through to the inner portion of the medulla, where they become the adrenal medulla {{#pmid:19683477|PMID19683477}}. Chromaffin cells are neuroendocrine cells and are found in the sympathetic ganglia and make up the majority of the adrenal medulla{{#pmid:19683477|PMID19683477}}. They synthesise and release a range of hormones in the body and arise from the temporary neural crest. The term chromaffin was inspired by the staining capacity of these cells when they came into contact with chrome salts. They make, store, export and use catecholamines, responsible for making noradrenaline and originate at the caudal region of somites 18-24 of the neural crest, also known as the adrenomedullary region {{#pmid:19683477|PMID19683477}}.

For cells to leave the neural crest and begin their migration, certain conditions need to be met, that is, the cells need to be loosely connected, their tight junctions becoming relaxed, initiated by "Slug protein" and a loss of N-Cadherin which also leads to the loosening of these junctions. The surrounding matrix as well as chemotactic and stem cell factors of the neural tube are then what dictates how the neural crest cells move, some proteins stopping their migration to that area and others encouraging the movement <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. After splitting apart, the first neural crest cells move ventrally and pass into the spaces between the somites and then, through the anterior portions of each segment until they arrive at the para-aortic sites, where they become the cells of the sympathetic ganglia and the adrenal medulla {{#pmid:19683477|PMID19683477}}. BMP-4 (bone morphogenetic protein 4) then acts on these neural crest cells, preventing them from becoming cells that have a neural function and causing them to become chromaffin cells at the adrenal medulla. Glucocorticoids then play a role in maintenance of chromaffin cells in postnatal life, this was only found recently, as previously it was thought that glucocorticoids were responsible entirely for the differentiation of neural crest cells into chromaffin, or adrenomedullary cells {{#pmid:23220335|PMID23220335}}.

===Developmental/adult function===
----
====Normal Structure and Function of the Adrenal Medulla====

The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The medulla contains secretory cells, rich vasculature with a high surface area and presynaptic sympathetitic ganglion cells. These cells secrete epinephrine and norepinephrine in response to various substances such as acetylcholine.

There are multiple cell types of in the adult adrenal medulla:

* Chromaffin cells
* Epinephrine cells
* Norepinephrine cells
* Small granule-containing cells (SGCs)

These cells also produce various other peptides such as substance P and neurotensin. The adrenal medulla also contains presynaptic sympathetic ganglion cells. {{#pmid:1694230|PMID1694230}}

These cells have unique neuroendocrine characteristics as a result of their neural-crest origin. They receive preganglionic innervation by thoracic splanchnic nerves, and could almost be considered a specialised sympathetic ganglion. With postganglgionic bodies, cells of the medulla are densely clustered around their vasculature for the secretion of hormones into the bloodstream to moderate the concentration of epinephrine and norepinephrine.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus. {{#pmid:11215683|PMID11215683}} [[File:Dd.jpg|400px|thumb|right|Adult Adrenal Glands in situ]]

====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses. {{#pmid:19396395|PMID19396395}}

----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

The 'story' of the Adrenal Medulla's neural crest tissue begins at the process of neurulation, the formation of the neural tube from the folding neural plate, which is comprised of developing ectoderm which is opposite to the primitive streak. It is here that several key chemical players are at work. The classic interpretation of Sonic Hedgehog (Shh) and Wnt signalling pathways as the only mediators here, has been shown to be incorrect. Research has uncovered other signallers such as:

*Bone-Morphogenic-Protein-4 (BMP4) for the regional expression of nervous system distinctions in the growing neural plate. This maintains two important embryonic trancription factors known as Paired-Box (PAX) Genes 3 and 7 which can allow for expression of neural crest markers HNK-1, SRY-Box (SOX) 8, 9 and 10 as the neural tube closes and the neural crest delaminates from the folding. {{#pmid:16688176|PMID16688176}}

*Slug via Wnt signalling, this allows for the loosening of gap junctions in the extracellular matrix surrounding the newly-formed neural tube and trunk of the embryo. This extracellular matrix has chemo-attractant molecules

[[File:Catecholamine_Synthesis.jpg|400px|thumb|right|Biochemical Cascade of Catecholamine Synthesis]]

The importance of Somitogenesis and Neural Crest come to a head when neural crest cells must migrate anteriorly past somites 18 to 24

Members of the SOX gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands. {{#pmid:18272785|PMID18272785}}

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well. {{#pmid:19396395|PMID19396395}}

===Abnormalities/abnormal development===
----

Abnormalities of the Adrenal Medulla are much less common than its mesoderm-derived shell of the Adrenal Gland. Three of the most notorious abnormalities of the Adrenal Medulla include:

* Pheochromocytomas
* Ganglioneuromas
* Neuroblastomas

Pheochromocytomas-

Ganglioneuromas-

Neuroblastomas-

Apart from these abnormalities, there are other pathologies that may be connected to the adrenal medulla. One such example is a pathology of the Organ of Zuckerkandl. Also known as the para-aortic body, the Organ of Zuckerkandl is a primarily-gestational organ comprised of chromaffin cells.

===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

====Chromaffin cells====
There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells{{#pmid:19377845|PMID19377845}}. The neural crest cells give rise to chromaffin cells of the adrenal medulla.

=====Rat Models=====
Previous research has reported that nueral crest cells differentiate into chromaffin cells around 19 days of gestation before forming the adrenal medulla{{#pmid:28684471|PMID2868441}}. Past research had also suggested that neural crest derived adrenal gland cells migrate using the sympathetic ganglia to the adrenal gland or preaortic ganglion, following different pathways, to reach their specific destination. However the results have shown that the pathways used to reach its destinations overlapped. This would suggest that there is a possibility of the cells using the same pathway to move from the beginning production to the destination that is the adrenal medulla (for chromaffin cells) and the preaortic ganglion (other cells involved in the sympathetic system).

One particular study done by M.Yamato in 2004, along with his fellow scientists attempted to study the migration of neural crest cells in Wistar rats. In order to observe the formation adrenal medulla from the neural crest cells during the embryonic period, Yamato used anti - tyrosine hydroxylase (TH) antiserum injected into the rat embryos between 13-17 days of gestation. The anti - TH antiserum stain allows the scientists to visualize the neural crest cells under a light microscope. Later three dimensional images were created. From the images observed between 13 to 15 days of gestation, the TH - positive cells can be seen to move from the dorsal to the adrenal primordium{{#pmid:15240937|PMID15240937}}. After 16 days it was observed that a capsule had formed in some parts and TH - positive cells had penetrated the adrenal gland{{#pmid:15240937|PMID15240937}}. At seventeen days, TH - positive cells can be seen collecting at the medial part of the adrenal gland. The reconstructed images also shows that at the later stages during the 16-17 days of gestation, the accumulation of TH - positive cells grow and in combination with cell division leads to the formation of the adrenal medulla.

(Pubmed: 15240937)

=====Chicken models=====
Chicken and rat models are often the most commonly used models when dealing with neural crest cells. In this particular review, collates multiple researchers results and presents evidence to discuss previous information suggesting that sympathetic neurons and chromaffin cells do not share a common progenitor{{#pmid:3693940|PMID3693940}}. The relevant study involved the use of cell cultures, Sympathoadrneal (SA) progenitor cells from embryonic(from chick embryos) and eary developmental stages were able to be procured. From these cultures it was easy to identify that glucocorticoids were crucial in the differentiation of SA cells into their derivatives, sympathetic neurons and chromaffin cells.

Another study conducted deals with the role of the BMP-4 protein and its importance in the development of the adrenal medullary cells, chromaffin cells{{#pmid:18945349|PMID18945349}}. Previous research had shown that BMP - 4 a growth factor is plays an important role in the regulation of chromaffin cell production{{#pmid:10679774|PMID10679774}}. The researchers incubated chick embryos for 3 - 9 embryonic days and dissected them to be used for tissue cultures. From these

Cell culture studies using isolated SA progenitor cells from embryonic and early postnatal sympathetic ganglia and adrenal gland have suggested that glucocorticoids play a crucial role in the diversification of SA cells into sympathetic neurons and chromaffin cells [22-24]; for reviews see [2,5,6,25], by suppressing a neuronal differentiation programme in SA cells destined to become chromaffin cells. However, analysis of mice deficient for the glucocorticoid receptor [26] or lacking an adrenal cortex [27] revealed that chromaffin cell differentiation was largely unimpaired suggesting that cues unrelated to glucocorticoid receptor signalling and the adrenal cortex triggered the chromaffin phenotype. This notion was corroborated and extended by studies showing that chick SA progenitors are already heterogeneous in terms of neurofilament-M (NF-M) expression prior to populating the adrenal gland and sympathetic ganglia [28] with presumptive neuronal cells co-expressing tyrosine hydroxylase (TH) and NF-M, and presumptive neuroendocrine cells being TH-positive and NF-M-negative. This indicated that specification of the respective phenotypes occurred either during migration or even prior to migration at the level of the NT.

A recent study by Krispin et al. [7,29] showed that in the trunk NT of avian embryos, precursors for sympathetic ganglia, Schwann cells, sensory dorsal root ganglionic neurons, and melanocytes leave the NT in successive, largely non-overlapping waves, some being already distinct while still residing in the NT. Although adrenal chromaffin cells were not addressed in this study, the results raised the possibility that sympathetic neurons and chromaffin cells might also already be distinct at the level of the NT. We therefore conducted single cell electroporations (EPs) of green fluorescent protein (GFP)-DNA into pre-migratory NC cells at the level of somites 18–24 (“adrenomedullary level”), where both chromaffin cells and sympathetic neurons arise [30]. The timing and location of EPs was directed to label the earliest progenitors that undergo delamination, previously shown to generate the sympathetic lineage [7,29], and the progeny of labelled cells was then analysed at E6 following homing to their target areas. Our results indicate that in more than 80% of the cases the progeny of a single labelled cell ends up in both sympathetic ganglia and adrenal gland, being mostly NF-M-negative in the adrenal gland and NF-M-positive in sympathetic ganglia. This suggests that chromaffin cells and sympathetic neurons share a common progenitor in the NT and that diversification of the phenotypes occurs during migration or assembly in primary sympathetic ganglia at the dorsal aorta.
The sympathoadrenal (SA) cell lineage is a major sub-lineage of the NC that gives rise to sympathetic neurons, intra- and extra-adrenal chromaffin cells, and the small intensely fluorescent (SIF) cells, which are intermediate between sympathetic neurons and chromaffin cells [2-5]. SA derivatives share several features, including the ability to synthesize, store, and release catecholamines, but also exhibit traits specific for each cell type, such as axons, dendrites, and neurofilaments, which are only found in sympathetic neurons but not chromaffin cells.

3693940

Prenatal adrenal gland development has been described in numerous published reports covering a wide variety of species, including the ox (Katznelson, 1966; Wrobel and Suss, 1999), sheep (Davies, 1950; Wintour et al., 1975; Upadhyay and Zamboni, 1982; Naaman‐Reperant and Durand, 1997; Grino, 2004), swine (Sokolov et al., 2006) and mouse (Waring, 1935; Ikeda et al., 1994; Sass, 1996; Nyska and Maronpot, 1999; Bland et al., 2003; Val et al., 2007). Adrenal gland development also has been extensively described for humans as well (Kolliker, 1879; Minot, 1892; Zuckerkandl, 1912; Wieman, 1920; Ikeda et al., 1981; Langlois et al., 2002; Hanley and Arit, 2006).

https://www.sciencedirect.com/science/article/pii/S0925477302004550
http://dev.biologists.org/content/develop/126/13/2935.full.pdf

===Current research (labs)===
----

==== Sympathoadrenal neural crest cells====

As explained above the adrenal medulla plays an important part in the autonomic system of an adult human. The chromaffin cells, in particular, are important neural crest derived cell that is closely related to the adrenal medulla. Previous findings have focused specifically on the mechanisms controlling the NCC migration and how these cells go on to form the different derivatives in their particular destinations in the embryo. For example, as previously explained studies have shown that chromaffin cells have been observed to move to the adrenal gland to form the medulla of the adrenal gland.

The findings presented until now have focused on the mechanisms controlling migration along the dorsolateral path. In comparison, our understanding of the mechanisms controlling NCC migration along the ventral path are complicated by the fact that this population comprises multiple precursors that form different derivatives in distinct regions of the embryo. For example, ventrally migrating NCCs either stop within the sclerotome in close association with the neural tube to form neurons and glia of the sensory nervous system (i.e. the dorsal root ganglia [DRG]), while other NCCs continue to migrate further ventrally to form the autonomic nervous system (i.e. sympathetic ganglia and chromaffin cells of the adrenal gland)<ref>Lumb, R., & Schwarz, Q. (2015). Sympathoadrenal neural crest cells: The known, unknown and forgotten?. Development, Growth & Differentiation, 57(2), 146-157. doi: 10.1111/dgd.12189</ref>.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/dgd.12189

Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type.

The autonomic nervous system is very important in understanding the human body and in turn understanding health. This report goes through a recent study that involves the adrenal medullary cells, in particular chromaffin cells, and their potential to be used to model certain pathological diseases related to these cells. This is part of a study that also involves neural crest cells and their ability to differentiate into multiple different types of cells.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693940/

===Glossary===
----
===Reference list===

2018 Group Project 1

2018-10-15T06:02:53Z

Z5113627: /* Molecular mechanisms/factors/genes */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===

----

The neural crest of an embryo differentiates and migrates to form various components of the body. One of these tissues is the medulla of the adrenal gland which is involved in the production of adrenalin and noradrenalin. This project will comprehensively outline the history of neural crest research, the embryonic developmental time course, tissue and organ structure, molecular mechanisms, abnormalities, animal models and current research.

===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.
[[File:NC Location.jpg|left|450px|thumb|The neural crest]]

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniably lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Embryonic origins===
----
[[File:Trunk_NCC_migration.jpg|left|450px|thumb|Trunk NCC migration]]
The adrenal gland is made up of the adrenal cortex and adrenal medulla, which both have different embryonic origins. The adrenal medulla arises from the neural crest tissue, found near the level of the coeliac plexus & sympathetic ganglion at somites 18-24 {{#pmid:16124976|PMID16124976}}. Specifically, this neural crest tissue comes from the trunk neural crest cells (see above figure to determine the approximate location in an embryo) <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
The trunk neural crest coordinates the development of the endocrine system, secretory cells, the peripheral nervous system and, to some degree, skeletal development, as well as innervation of the intestine {{#pmid: 28287247|PMID 28287247}}. The trunk neural cells arise caudally, undergo an epithelial to mesenchymal transition and follow three migratory pathways {{#pmid:20399766|PMID20399766}}.
[[File:Differentiation_of_NCC.jpg|left|580px|thumb|Differentiation of chromaffin cells]]
- A dorsolateral pathway (between ectoderm and somites), these become melanocytes, travel up to the point of the dermis and become a major part of the hair follicles and skin <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
- A ventrolateral pathway (through the somites)
- A ventromedial pathway (between neural tube and posterior schlerotome){{#pmid:20399766|PMID20399766}}.

Migration of neural crest cells from the sympathetic ganglion is what leads to the development of the adrenal medulla. In week 8 of development, immature cells called neuroblasts migrate through to the inner portion of the medulla, where they become the adrenal medulla {{#pmid:19683477|PMID19683477}}. Chromaffin cells are neuroendocrine cells and are found in the sympathetic ganglia and make up the majority of the adrenal medulla{{#pmid:19683477|PMID19683477}}. They synthesise and release a range of hormones in the body and arise from the temporary neural crest. The term chromaffin was inspired by the staining capacity of these cells when they came into contact with chrome salts. They make, store, export and use catecholamines, responsible for making noradrenaline and originate at the caudal region of somites 18-24 of the neural crest, also known as the adrenomedullary region {{#pmid:19683477|PMID19683477}}.

For cells to leave the neural crest and begin their migration, certain conditions need to be met, that is, the cells need to be loosely connected, their tight junctions becoming relaxed, initiated by "Slug protein" and a loss of N-Cadherin which also leads to the loosening of these junctions. The surrounding matrix as well as chemotactic and stem cell factors of the neural tube are then what dictates how the neural crest cells move, some proteins stopping their migration to that area and others encouraging the movement <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. After splitting apart, the first neural crest cells move ventrally and pass into the spaces between the somites and then, through the anterior portions of each segment until they arrive at the para-aortic sites, where they become the cells of the sympathetic ganglia and the adrenal medulla {{#pmid:19683477|PMID19683477}}. BMP-4 (bone morphogenetic protein 4) then acts on these neural crest cells, preventing them from becoming cells that have a neural function and causing them to become chromaffin cells at the adrenal medulla. Glucocorticoids then play a role in maintenance of chromaffin cells in postnatal life, this was only found recently, as previously it was thought that glucocorticoids were responsible entirely for the differentiation of neural crest cells into chromaffin, or adrenomedullary cells {{#pmid:23220335|PMID23220335}}.

===Developmental/adult function===
----
====Normal Structure and Function of the Adrenal Medulla====

The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The medulla contains secretory cells called chromaffin cells, due to the agents they produce when oxidised, such as chromate. These cells secrete epinephrine and norepinephrine in response to various substances such as acetylcholine.

There are three types of cells in the adult adrenal medulla:

* Epinephrine cells
* Norepinephrine cells
* Small granule-containing cells (SGCs)

These cells also produce various other peptides such as substance P and neurotensin. The adrenal medulla also contains presynaptic sympathetic ganglion cells. {{#pmid:1694230|PMID1694230}}

These cells have unique neuroendocrine characteristics as a result of their neural-crest origin. They receive preganglionic innervation by thoracic splanchnic nerves, and could almost be considered a specialised sympathetic ganglion. With postganglgionic bodies, cells of the medulla are densely clustered around their vasculature for the secretion of hormones into the bloodstream to moderate the concentration of epinephrine and norepinephrine.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus. {{#pmid:11215683|PMID11215683}} [[File:Dd.jpg|400px|thumb|right|Adult Adrenal Glands in situ]]

====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses. {{#pmid:19396395|PMID19396395}}

----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

The 'story' of the Adrenal Medulla's neural crest tissue begins at the process of neurulation, the formation of the neural tube from the folding neural plate, which is comprised of developing ectoderm which is opposite to the primitive streak. It is here that several key chemical players are at work. The classic interpretation of Sonic Hedgehog (Shh) and Wnt signalling pathways as the only mediators here, has been shown to be incorrect. Research has uncovered other signallers such as:

*Bone-Morphogenic-Protein-4 (BMP4) for the regional expression of nervous system distinctions in the growing neural plate. This maintains two important embryonic trancription factors known as Paired-Box (PAX) Genes 3 and 7 which can allow for expression of neural crest markers HNK-1, SRY-Box (SOX) 8, 9 and 10 as the neural tube closes and the neural crest delaminates from the folding. {{#pmid:16688176|PMID16688176}}

*Slug via Wnt signalling, this allows for the loosening of gap junctions in the extracellular matrix surrounding the newly-formed neural tube and trunk of the embryo. This extracellular matrix has chemo-attractant molecules

[[File:Catecholamine_Synthesis.jpg|400px|thumb|right|Biochemical Cascade of Catecholamine Synthesis]]

The importance of Somitogenesis and Neural Crest come to a head when neural crest cells must migrate anteriorly past somites 18 to 24

Members of the SOX gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands. {{#pmid:18272785|PMID18272785}}

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well. {{#pmid:19396395|PMID19396395}}

===Abnormalities/abnormal development===
----

Abnormalities of the Adrenal Medulla are much less common than its mesoderm-derived shell of the Adrenal Gland. Three of the most notorious abnormalities of the Adrenal Medulla include:

* Pheochromocytomas
* Ganglioneuromas
* Neuroblastomas

Pheochromocytomas-

Ganglioneuromas-

Neuroblastomas-

Apart from these abnormalities, there are other pathologies that may be connected to the adrenal medulla. One such example is a pathology of the Organ of Zuckerkandl. Also known as the para-aortic body, the Organ of Zuckerkandl is a primarily-gestational organ comprised of chromaffin cells.

===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

====Chromaffin cells====
There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells{{#pmid:19377845|PMID19377845}}. The neural crest cells give rise to chromaffin cells of the adrenal medulla.

=====Rat Models=====
Previous research has reported that nueral crest cells differentiate into chromaffin cells around 19 days of gestation before forming the adrenal medulla{{#pmid:28684471|PMID2868441}}. Past research had also suggested that neural crest derived adrenal gland cells migrate using the sympathetic ganglia to the adrenal gland or preaortic ganglion, following different pathways, to reach their specific destination. However the results have shown that the pathways used to reach its destinations overlapped. This would suggest that there is a possibility of the cells using the same pathway to move from the beginning production to the destination that is the adrenal medulla (for chromaffin cells) and the preaortic ganglion (other cells involved in the sympathetic system).

One particular study done by M.Yamato in 2004, along with his fellow scientists attempted to study the migration of neural crest cells in Wistar rats. In order to observe the formation adrenal medulla from the neural crest cells during the embryonic period, Yamato used anti - tyrosine hydroxylase (TH) antiserum injected into the rat embryos between 13-17 days of gestation. The anti - TH antiserum stain allows the scientists to visualize the neural crest cells under a light microscope. Later three dimensional images were created. From the images observed between 13 to 15 days of gestation, the TH - positive cells can be seen to move from the dorsal to the adrenal primordium{{#pmid:15240937|PMID15240937}}. After 16 days it was observed that a capsule had formed in some parts and TH - positive cells had penetrated the adrenal gland{{#pmid:15240937|PMID15240937}}. At seventeen days, TH - positive cells can be seen collecting at the medial part of the adrenal gland. The reconstructed images also shows that at the later stages during the 16-17 days of gestation, the accumulation of TH - positive cells grow and in combination with cell division leads to the formation of the adrenal medulla.

(Pubmed: 15240937)

=====Chicken models=====
Chicken and rat models are often the most commonly used models when dealing with neural crest cells. In this particular review, collates multiple researchers results and presents evidence to discuss previous information suggesting that sympathetic neurons and chromaffin cells do not share a common progenitor{{#pmid:3693940|PMID3693940}}. The relevant study involved the use of cell cultures, Sympathoadrneal (SA) progenitor cells from embryonic(from chick embryos) and eary developmental stages were able to be procured. From these cultures it was easy to identify that glucocorticoids were crucial in the differentiation of SA cells into their derivatives, sympathetic neurons and chromaffin cells.

Another study conducted deals with the role of the BMP-4 protein and its importance in the development of the adrenal medullary cells, chromaffin cells{{#pmid:18945349|PMID18945349}}. Previous research had shown that BMP - 4 a growth factor is plays an important role in the regulation of chromaffin cell production{{#pmid:10679774|PMID10679774}}. The researchers incubated chick embryos for 3 - 9 embryonic days and dissected them to be used for tissue cultures. From these

Cell culture studies using isolated SA progenitor cells from embryonic and early postnatal sympathetic ganglia and adrenal gland have suggested that glucocorticoids play a crucial role in the diversification of SA cells into sympathetic neurons and chromaffin cells [22-24]; for reviews see [2,5,6,25], by suppressing a neuronal differentiation programme in SA cells destined to become chromaffin cells. However, analysis of mice deficient for the glucocorticoid receptor [26] or lacking an adrenal cortex [27] revealed that chromaffin cell differentiation was largely unimpaired suggesting that cues unrelated to glucocorticoid receptor signalling and the adrenal cortex triggered the chromaffin phenotype. This notion was corroborated and extended by studies showing that chick SA progenitors are already heterogeneous in terms of neurofilament-M (NF-M) expression prior to populating the adrenal gland and sympathetic ganglia [28] with presumptive neuronal cells co-expressing tyrosine hydroxylase (TH) and NF-M, and presumptive neuroendocrine cells being TH-positive and NF-M-negative. This indicated that specification of the respective phenotypes occurred either during migration or even prior to migration at the level of the NT.

A recent study by Krispin et al. [7,29] showed that in the trunk NT of avian embryos, precursors for sympathetic ganglia, Schwann cells, sensory dorsal root ganglionic neurons, and melanocytes leave the NT in successive, largely non-overlapping waves, some being already distinct while still residing in the NT. Although adrenal chromaffin cells were not addressed in this study, the results raised the possibility that sympathetic neurons and chromaffin cells might also already be distinct at the level of the NT. We therefore conducted single cell electroporations (EPs) of green fluorescent protein (GFP)-DNA into pre-migratory NC cells at the level of somites 18–24 (“adrenomedullary level”), where both chromaffin cells and sympathetic neurons arise [30]. The timing and location of EPs was directed to label the earliest progenitors that undergo delamination, previously shown to generate the sympathetic lineage [7,29], and the progeny of labelled cells was then analysed at E6 following homing to their target areas. Our results indicate that in more than 80% of the cases the progeny of a single labelled cell ends up in both sympathetic ganglia and adrenal gland, being mostly NF-M-negative in the adrenal gland and NF-M-positive in sympathetic ganglia. This suggests that chromaffin cells and sympathetic neurons share a common progenitor in the NT and that diversification of the phenotypes occurs during migration or assembly in primary sympathetic ganglia at the dorsal aorta.
The sympathoadrenal (SA) cell lineage is a major sub-lineage of the NC that gives rise to sympathetic neurons, intra- and extra-adrenal chromaffin cells, and the small intensely fluorescent (SIF) cells, which are intermediate between sympathetic neurons and chromaffin cells [2-5]. SA derivatives share several features, including the ability to synthesize, store, and release catecholamines, but also exhibit traits specific for each cell type, such as axons, dendrites, and neurofilaments, which are only found in sympathetic neurons but not chromaffin cells.

3693940

Prenatal adrenal gland development has been described in numerous published reports covering a wide variety of species, including the ox (Katznelson, 1966; Wrobel and Suss, 1999), sheep (Davies, 1950; Wintour et al., 1975; Upadhyay and Zamboni, 1982; Naaman‐Reperant and Durand, 1997; Grino, 2004), swine (Sokolov et al., 2006) and mouse (Waring, 1935; Ikeda et al., 1994; Sass, 1996; Nyska and Maronpot, 1999; Bland et al., 2003; Val et al., 2007). Adrenal gland development also has been extensively described for humans as well (Kolliker, 1879; Minot, 1892; Zuckerkandl, 1912; Wieman, 1920; Ikeda et al., 1981; Langlois et al., 2002; Hanley and Arit, 2006).

https://www.sciencedirect.com/science/article/pii/S0925477302004550
http://dev.biologists.org/content/develop/126/13/2935.full.pdf

===Current research (labs)===
----

==== Sympathoadrenal neural crest cells====

As explained above the adrenal medulla plays an important part in the autonomic system of an adult human. The chromaffin cells, in particular, are important neural crest derived cell that is closely related to the adrenal medulla. Previous findings have focused specifically on the mechanisms controlling the NCC migration and how these cells go on to form the different derivatives in their particular destinations in the embryo. For example, as previously explained studies have shown that chromaffin cells have been observed to move to the adrenal gland to form the medulla of the adrenal gland.

The findings presented until now have focused on the mechanisms controlling migration along the dorsolateral path. In comparison, our understanding of the mechanisms controlling NCC migration along the ventral path are complicated by the fact that this population comprises multiple precursors that form different derivatives in distinct regions of the embryo. For example, ventrally migrating NCCs either stop within the sclerotome in close association with the neural tube to form neurons and glia of the sensory nervous system (i.e. the dorsal root ganglia [DRG]), while other NCCs continue to migrate further ventrally to form the autonomic nervous system (i.e. sympathetic ganglia and chromaffin cells of the adrenal gland)<ref>Lumb, R., & Schwarz, Q. (2015). Sympathoadrenal neural crest cells: The known, unknown and forgotten?. Development, Growth & Differentiation, 57(2), 146-157. doi: 10.1111/dgd.12189</ref>.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/dgd.12189

Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type.

The autonomic nervous system is very important in understanding the human body and in turn understanding health. This report goes through a recent study that involves the adrenal medullary cells, in particular chromaffin cells, and their potential to be used to model certain pathological diseases related to these cells. This is part of a study that also involves neural crest cells and their ability to differentiate into multiple different types of cells.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693940/

===Glossary===
----
===Reference list===

2018 Group Project 1

2018-10-15T06:02:31Z

Z5113627: /* Genes and Transcription Factors Involved with the Adrenal Medulla's Development */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===

----

The neural crest of an embryo differentiates and migrates to form various components of the body. One of these tissues is the medulla of the adrenal gland which is involved in the production of adrenalin and noradrenalin. This project will comprehensively outline the history of neural crest research, the embryonic developmental time course, tissue and organ structure, molecular mechanisms, abnormalities, animal models and current research.

===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.
[[File:NC Location.jpg|left|450px|thumb|The neural crest]]

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniably lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Embryonic origins===
----
[[File:Trunk_NCC_migration.jpg|left|450px|thumb|Trunk NCC migration]]
The adrenal gland is made up of the adrenal cortex and adrenal medulla, which both have different embryonic origins. The adrenal medulla arises from the neural crest tissue, found near the level of the coeliac plexus & sympathetic ganglion at somites 18-24 {{#pmid:16124976|PMID16124976}}. Specifically, this neural crest tissue comes from the trunk neural crest cells (see above figure to determine the approximate location in an embryo) <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
The trunk neural crest coordinates the development of the endocrine system, secretory cells, the peripheral nervous system and, to some degree, skeletal development, as well as innervation of the intestine {{#pmid: 28287247|PMID 28287247}}. The trunk neural cells arise caudally, undergo an epithelial to mesenchymal transition and follow three migratory pathways {{#pmid:20399766|PMID20399766}}.
[[File:Differentiation_of_NCC.jpg|left|580px|thumb|Differentiation of chromaffin cells]]
- A dorsolateral pathway (between ectoderm and somites), these become melanocytes, travel up to the point of the dermis and become a major part of the hair follicles and skin <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
- A ventrolateral pathway (through the somites)
- A ventromedial pathway (between neural tube and posterior schlerotome){{#pmid:20399766|PMID20399766}}.

Migration of neural crest cells from the sympathetic ganglion is what leads to the development of the adrenal medulla. In week 8 of development, immature cells called neuroblasts migrate through to the inner portion of the medulla, where they become the adrenal medulla {{#pmid:19683477|PMID19683477}}. Chromaffin cells are neuroendocrine cells and are found in the sympathetic ganglia and make up the majority of the adrenal medulla{{#pmid:19683477|PMID19683477}}. They synthesise and release a range of hormones in the body and arise from the temporary neural crest. The term chromaffin was inspired by the staining capacity of these cells when they came into contact with chrome salts. They make, store, export and use catecholamines, responsible for making noradrenaline and originate at the caudal region of somites 18-24 of the neural crest, also known as the adrenomedullary region {{#pmid:19683477|PMID19683477}}.

For cells to leave the neural crest and begin their migration, certain conditions need to be met, that is, the cells need to be loosely connected, their tight junctions becoming relaxed, initiated by "Slug protein" and a loss of N-Cadherin which also leads to the loosening of these junctions. The surrounding matrix as well as chemotactic and stem cell factors of the neural tube are then what dictates how the neural crest cells move, some proteins stopping their migration to that area and others encouraging the movement <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. After splitting apart, the first neural crest cells move ventrally and pass into the spaces between the somites and then, through the anterior portions of each segment until they arrive at the para-aortic sites, where they become the cells of the sympathetic ganglia and the adrenal medulla {{#pmid:19683477|PMID19683477}}. BMP-4 (bone morphogenetic protein 4) then acts on these neural crest cells, preventing them from becoming cells that have a neural function and causing them to become chromaffin cells at the adrenal medulla. Glucocorticoids then play a role in maintenance of chromaffin cells in postnatal life, this was only found recently, as previously it was thought that glucocorticoids were responsible entirely for the differentiation of neural crest cells into chromaffin, or adrenomedullary cells {{#pmid:23220335|PMID23220335}}.

===Developmental/adult function===
----
====Normal Structure and Function of the Adrenal Medulla====

The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The medulla contains secretory cells called chromaffin cells, due to the agents they produce when oxidised, such as chromate. These cells secrete epinephrine and norepinephrine in response to various substances such as acetylcholine.

There are three types of cells in the adult adrenal medulla:

* Epinephrine cells
* Norepinephrine cells
* Small granule-containing cells (SGCs)

These cells also produce various other peptides such as substance P and neurotensin. The adrenal medulla also contains presynaptic sympathetic ganglion cells. {{#pmid:1694230|PMID1694230}}

These cells have unique neuroendocrine characteristics as a result of their neural-crest origin. They receive preganglionic innervation by thoracic splanchnic nerves, and could almost be considered a specialised sympathetic ganglion. With postganglgionic bodies, cells of the medulla are densely clustered around their vasculature for the secretion of hormones into the bloodstream to moderate the concentration of epinephrine and norepinephrine.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus. {{#pmid:11215683|PMID11215683}} [[File:Dd.jpg|400px|thumb|right|Adult Adrenal Glands in situ]]

====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses. {{#pmid:19396395|PMID19396395}}

----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

The 'story' of the Adrenal Medulla's neural crest tissue begins at the process of neurulation, the formation of the neural tube from the folding neural plate, which is comprised of developing ectoderm which is opposite to the primitive streak. It is here that several key chemical players are at work. The classic interpretation of Sonic Hedgehog (Shh) and Wnt signalling pathways as the only mediators here, has been shown to be incorrect. Research has uncovered other signallers such as:

*Bone-Morphogenic-Protein-4 (BMP4) for the regional expression of nervous system distinctions in the growing neural plate. This maintains two important embryonic trancription factors known as Paired-Box (PAX) Genes 3 and 7 which can allow for expression of neural crest markers HNK-1, SRY-Box (SOX) 8, 9 and 10 as the neural tube closes and the neural crest delaminates from the folding. {{#pmid:16688176|PMID16688176}}

*Slug via Wnt signalling, this allows for the loosening of gap junctions in the extracellular matrix surrounding the newly-formed neural tube and trunk of the embryo. This extracellular matrix has chemo-attractant molecules

[[File:Catecholamine_Synthesis.jpg|400px|thumb|right|Biochemical Cascade of Catecholamine Synthesis]]

The importance of Somitogenesis and Neural Crest come to a head when neural crest cells must migrate anteriorly past somites 18 to 24

Members of the SOX gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands. {{#pmid:18272785|PMID18272785}}

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well. {{#pmid:19396395|PMID19396395}}

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291442/
https://www.ncbi.nlm.nih.gov/pubmed/19396395

===Abnormalities/abnormal development===
----

Abnormalities of the Adrenal Medulla are much less common than its mesoderm-derived shell of the Adrenal Gland. Three of the most notorious abnormalities of the Adrenal Medulla include:

* Pheochromocytomas
* Ganglioneuromas
* Neuroblastomas

Pheochromocytomas-

Ganglioneuromas-

Neuroblastomas-

Apart from these abnormalities, there are other pathologies that may be connected to the adrenal medulla. One such example is a pathology of the Organ of Zuckerkandl. Also known as the para-aortic body, the Organ of Zuckerkandl is a primarily-gestational organ comprised of chromaffin cells.

===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

====Chromaffin cells====
There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells{{#pmid:19377845|PMID19377845}}. The neural crest cells give rise to chromaffin cells of the adrenal medulla.

=====Rat Models=====
Previous research has reported that nueral crest cells differentiate into chromaffin cells around 19 days of gestation before forming the adrenal medulla{{#pmid:28684471|PMID2868441}}. Past research had also suggested that neural crest derived adrenal gland cells migrate using the sympathetic ganglia to the adrenal gland or preaortic ganglion, following different pathways, to reach their specific destination. However the results have shown that the pathways used to reach its destinations overlapped. This would suggest that there is a possibility of the cells using the same pathway to move from the beginning production to the destination that is the adrenal medulla (for chromaffin cells) and the preaortic ganglion (other cells involved in the sympathetic system).

One particular study done by M.Yamato in 2004, along with his fellow scientists attempted to study the migration of neural crest cells in Wistar rats. In order to observe the formation adrenal medulla from the neural crest cells during the embryonic period, Yamato used anti - tyrosine hydroxylase (TH) antiserum injected into the rat embryos between 13-17 days of gestation. The anti - TH antiserum stain allows the scientists to visualize the neural crest cells under a light microscope. Later three dimensional images were created. From the images observed between 13 to 15 days of gestation, the TH - positive cells can be seen to move from the dorsal to the adrenal primordium{{#pmid:15240937|PMID15240937}}. After 16 days it was observed that a capsule had formed in some parts and TH - positive cells had penetrated the adrenal gland{{#pmid:15240937|PMID15240937}}. At seventeen days, TH - positive cells can be seen collecting at the medial part of the adrenal gland. The reconstructed images also shows that at the later stages during the 16-17 days of gestation, the accumulation of TH - positive cells grow and in combination with cell division leads to the formation of the adrenal medulla.

(Pubmed: 15240937)

=====Chicken models=====
Chicken and rat models are often the most commonly used models when dealing with neural crest cells. In this particular review, collates multiple researchers results and presents evidence to discuss previous information suggesting that sympathetic neurons and chromaffin cells do not share a common progenitor{{#pmid:3693940|PMID3693940}}. The relevant study involved the use of cell cultures, Sympathoadrneal (SA) progenitor cells from embryonic(from chick embryos) and eary developmental stages were able to be procured. From these cultures it was easy to identify that glucocorticoids were crucial in the differentiation of SA cells into their derivatives, sympathetic neurons and chromaffin cells.

Another study conducted deals with the role of the BMP-4 protein and its importance in the development of the adrenal medullary cells, chromaffin cells{{#pmid:18945349|PMID18945349}}. Previous research had shown that BMP - 4 a growth factor is plays an important role in the regulation of chromaffin cell production{{#pmid:10679774|PMID10679774}}. The researchers incubated chick embryos for 3 - 9 embryonic days and dissected them to be used for tissue cultures. From these

Cell culture studies using isolated SA progenitor cells from embryonic and early postnatal sympathetic ganglia and adrenal gland have suggested that glucocorticoids play a crucial role in the diversification of SA cells into sympathetic neurons and chromaffin cells [22-24]; for reviews see [2,5,6,25], by suppressing a neuronal differentiation programme in SA cells destined to become chromaffin cells. However, analysis of mice deficient for the glucocorticoid receptor [26] or lacking an adrenal cortex [27] revealed that chromaffin cell differentiation was largely unimpaired suggesting that cues unrelated to glucocorticoid receptor signalling and the adrenal cortex triggered the chromaffin phenotype. This notion was corroborated and extended by studies showing that chick SA progenitors are already heterogeneous in terms of neurofilament-M (NF-M) expression prior to populating the adrenal gland and sympathetic ganglia [28] with presumptive neuronal cells co-expressing tyrosine hydroxylase (TH) and NF-M, and presumptive neuroendocrine cells being TH-positive and NF-M-negative. This indicated that specification of the respective phenotypes occurred either during migration or even prior to migration at the level of the NT.

A recent study by Krispin et al. [7,29] showed that in the trunk NT of avian embryos, precursors for sympathetic ganglia, Schwann cells, sensory dorsal root ganglionic neurons, and melanocytes leave the NT in successive, largely non-overlapping waves, some being already distinct while still residing in the NT. Although adrenal chromaffin cells were not addressed in this study, the results raised the possibility that sympathetic neurons and chromaffin cells might also already be distinct at the level of the NT. We therefore conducted single cell electroporations (EPs) of green fluorescent protein (GFP)-DNA into pre-migratory NC cells at the level of somites 18–24 (“adrenomedullary level”), where both chromaffin cells and sympathetic neurons arise [30]. The timing and location of EPs was directed to label the earliest progenitors that undergo delamination, previously shown to generate the sympathetic lineage [7,29], and the progeny of labelled cells was then analysed at E6 following homing to their target areas. Our results indicate that in more than 80% of the cases the progeny of a single labelled cell ends up in both sympathetic ganglia and adrenal gland, being mostly NF-M-negative in the adrenal gland and NF-M-positive in sympathetic ganglia. This suggests that chromaffin cells and sympathetic neurons share a common progenitor in the NT and that diversification of the phenotypes occurs during migration or assembly in primary sympathetic ganglia at the dorsal aorta.
The sympathoadrenal (SA) cell lineage is a major sub-lineage of the NC that gives rise to sympathetic neurons, intra- and extra-adrenal chromaffin cells, and the small intensely fluorescent (SIF) cells, which are intermediate between sympathetic neurons and chromaffin cells [2-5]. SA derivatives share several features, including the ability to synthesize, store, and release catecholamines, but also exhibit traits specific for each cell type, such as axons, dendrites, and neurofilaments, which are only found in sympathetic neurons but not chromaffin cells.

3693940

Prenatal adrenal gland development has been described in numerous published reports covering a wide variety of species, including the ox (Katznelson, 1966; Wrobel and Suss, 1999), sheep (Davies, 1950; Wintour et al., 1975; Upadhyay and Zamboni, 1982; Naaman‐Reperant and Durand, 1997; Grino, 2004), swine (Sokolov et al., 2006) and mouse (Waring, 1935; Ikeda et al., 1994; Sass, 1996; Nyska and Maronpot, 1999; Bland et al., 2003; Val et al., 2007). Adrenal gland development also has been extensively described for humans as well (Kolliker, 1879; Minot, 1892; Zuckerkandl, 1912; Wieman, 1920; Ikeda et al., 1981; Langlois et al., 2002; Hanley and Arit, 2006).

https://www.sciencedirect.com/science/article/pii/S0925477302004550
http://dev.biologists.org/content/develop/126/13/2935.full.pdf

===Current research (labs)===
----

==== Sympathoadrenal neural crest cells====

As explained above the adrenal medulla plays an important part in the autonomic system of an adult human. The chromaffin cells, in particular, are important neural crest derived cell that is closely related to the adrenal medulla. Previous findings have focused specifically on the mechanisms controlling the NCC migration and how these cells go on to form the different derivatives in their particular destinations in the embryo. For example, as previously explained studies have shown that chromaffin cells have been observed to move to the adrenal gland to form the medulla of the adrenal gland.

The findings presented until now have focused on the mechanisms controlling migration along the dorsolateral path. In comparison, our understanding of the mechanisms controlling NCC migration along the ventral path are complicated by the fact that this population comprises multiple precursors that form different derivatives in distinct regions of the embryo. For example, ventrally migrating NCCs either stop within the sclerotome in close association with the neural tube to form neurons and glia of the sensory nervous system (i.e. the dorsal root ganglia [DRG]), while other NCCs continue to migrate further ventrally to form the autonomic nervous system (i.e. sympathetic ganglia and chromaffin cells of the adrenal gland)<ref>Lumb, R., & Schwarz, Q. (2015). Sympathoadrenal neural crest cells: The known, unknown and forgotten?. Development, Growth & Differentiation, 57(2), 146-157. doi: 10.1111/dgd.12189</ref>.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/dgd.12189

Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type.

The autonomic nervous system is very important in understanding the human body and in turn understanding health. This report goes through a recent study that involves the adrenal medullary cells, in particular chromaffin cells, and their potential to be used to model certain pathological diseases related to these cells. This is part of a study that also involves neural crest cells and their ability to differentiate into multiple different types of cells.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693940/

===Glossary===
----
===Reference list===

2018 Group Project 1

2018-10-15T05:44:23Z

Z5113627: /* Genes and Transcription Factors Involved with the Adrenal Medulla's Development */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===

----

The neural crest of an embryo differentiates and migrates to form various components of the body. One of these tissues is the medulla of the adrenal gland which is involved in the production of adrenalin and noradrenalin. This project will comprehensively outline the history of neural crest research, the embryonic developmental time course, tissue and organ structure, molecular mechanisms, abnormalities, animal models and current research.

===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.
[[File:NC Location.jpg|left|450px|thumb|The neural crest]]

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniably lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Embryonic origins===
----
[[File:Trunk_NCC_migration.jpg|left|450px|thumb|Trunk NCC migration]]
The adrenal gland is made up of the adrenal cortex and adrenal medulla, which both have different embryonic origins. The adrenal medulla arises from the neural crest tissue, found near the level of the coeliac plexus & sympathetic ganglion at somites 18-24 {{#pmid:16124976|PMID16124976}}. Specifically, this neural crest tissue comes from the trunk neural crest cells (see above figure to determine the approximate location in an embryo) <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
The trunk neural crest coordinates the development of the endocrine system, secretory cells, the peripheral nervous system and, to some degree, skeletal development, as well as innervation of the intestine {{#pmid: 28287247|PMID 28287247}}. The trunk neural cells arise caudally, undergo an epithelial to mesenchymal transition and follow three migratory pathways {{#pmid:20399766|PMID20399766}}.
[[File:Differentiation_of_NCC.jpg|left|580px|thumb|Differentiation of chromaffin cells]]
- A dorsolateral pathway (between ectoderm and somites), these become melanocytes, travel up to the point of the dermis and become a major part of the hair follicles and skin <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
- A ventrolateral pathway (through the somites)
- A ventromedial pathway (between neural tube and posterior schlerotome){{#pmid:20399766|PMID20399766}}.

Migration of neural crest cells from the sympathetic ganglion is what leads to the development of the adrenal medulla. In week 8 of development, immature cells called neuroblasts migrate through to the inner portion of the medulla, where they become the adrenal medulla {{#pmid:19683477|PMID19683477}}. Chromaffin cells are neuroendocrine cells and are found in the sympathetic ganglia and make up the majority of the adrenal medulla{{#pmid:19683477|PMID19683477}}. They synthesise and release a range of hormones in the body and arise from the temporary neural crest. The term chromaffin was inspired by the staining capacity of these cells when they came into contact with chrome salts. They make, store, export and use catecholamines, responsible for making noradrenaline and originate at the caudal region of somites 18-24 of the neural crest, also known as the adrenomedullary region {{#pmid:19683477|PMID19683477}}.

For cells to leave the neural crest and begin their migration, certain conditions need to be met, that is, the cells need to be loosely connected, their tight junctions becoming relaxed, initiated by "Slug protein" and a loss of N-Cadherin which also leads to the loosening of these junctions. The surrounding matrix as well as chemotactic and stem cell factors of the neural tube are then what dictates how the neural crest cells move, some proteins stopping their migration to that area and others encouraging the movement <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. After splitting apart, the first neural crest cells move ventrally and pass into the spaces between the somites and then, through the anterior portions of each segment until they arrive at the para-aortic sites, where they become the cells of the sympathetic ganglia and the adrenal medulla {{#pmid:19683477|PMID19683477}}. BMP-4 (bone morphogenetic protein 4) then acts on these neural crest cells, preventing them from becoming cells that have a neural function and causing them to become chromaffin cells at the adrenal medulla. Glucocorticoids then play a role in maintenance of chromaffin cells in postnatal life, this was only found recently, as previously it was thought that glucocorticoids were responsible entirely for the differentiation of neural crest cells into chromaffin, or adrenomedullary cells {{#pmid:23220335|PMID23220335}}.

===Developmental/adult function===
----
====Normal Structure and Function of the Adrenal Medulla====

The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The medulla contains secretory cells called chromaffin cells, due to the agents they produce when oxidised, such as chromate. These cells secrete epinephrine and norepinephrine in response to various substances such as acetylcholine.

There are three types of cells in the adult adrenal medulla:

* Epinephrine cells
* Norepinephrine cells
* Small granule-containing cells (SGCs)

These cells also produce various other peptides such as substance P and neurotensin. The adrenal medulla also contains presynaptic sympathetic ganglion cells. {{#pmid:1694230|PMID1694230}}

These cells have unique neuroendocrine characteristics as a result of their neural-crest origin. They receive preganglionic innervation by thoracic splanchnic nerves, and could almost be considered a specialised sympathetic ganglion. With postganglgionic bodies, cells of the medulla are densely clustered around their vasculature for the secretion of hormones into the bloodstream to moderate the concentration of epinephrine and norepinephrine.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus. {{#pmid:11215683|PMID11215683}} [[File:Dd.jpg|400px|thumb|right|Adult Adrenal Glands in situ]]

====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses. {{#pmid:19396395|PMID19396395}}

----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

The 'story' of the Adrenal Medulla's neural crest tissue begins at the process of neurulation, the formation of the neural tube from the folding neural plate, which is comprised of developing ectoderm which is opposite to the primitive streak. It is here that several key chemical players are at work. The classic interpretation of Sonic Hedgehog (Shh) and Wnt signalling pathways as the only mediators here, has been shown to be incorrect. Research has uncovered other signallers such as:

*Bone-Morphogenic-Protein-4 (BMP4) for the regional expression of nervous system distinctions in the growing neural plate. This maintains two important embryonic trancription factors known as Paired-Box (PAX) Genes 3 and 7 which can allow for expression of neural crest markers HNK-1, SRY-Box (SOX) 8, 9 and 10 as the neural tube closes and the neural crest delaminates from the folding. {{#pmid:16688176|PMID16688176}}

*Slug via Wnt signalling, this allows for the loosening of gap junctions in the extracellular matrix surrounding the newly-formed neural tube and trunk of the embryo. This extracellular matrix has chemo-attractant molecules

[[File:Catecholamine_Synthesis.jpg|400px|thumb|right|Biochemical Cascade of Catecholamine Synthesis]]

The importance of Somitogenesis and Neural Crest come to a head when neural crest cells must migrate anteriorly past somites 18 to 24

Members of the SOX gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands.

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291442/
https://www.ncbi.nlm.nih.gov/pubmed/19396395

===Abnormalities/abnormal development===
----

Abnormalities of the Adrenal Medulla are much less common than its mesoderm-derived shell of the Adrenal Gland. Three of the most notorious abnormalities of the Adrenal Medulla include:

* Pheochromocytomas
* Ganglioneuromas
* Neuroblastomas

Pheochromocytomas-

Ganglioneuromas-

Neuroblastomas-

Apart from these abnormalities, there are other pathologies that may be connected to the adrenal medulla. One such example is a pathology of the Organ of Zuckerkandl. Also known as the para-aortic body, the Organ of Zuckerkandl is a primarily-gestational organ comprised of chromaffin cells.

===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

====Chromaffin cells====
There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells{{#pmid:19377845|PMID19377845}}. The neural crest cells give rise to chromaffin cells of the adrenal medulla.

=====Rat Models=====
Previous research has reported that nueral crest cells differentiate into chromaffin cells around 19 days of gestation before forming the adrenal medulla{{#pmid:28684471|PMID2868441}}. Past research had also suggested that neural crest derived adrenal gland cells migrate using the sympathetic ganglia to the adrenal gland or preaortic ganglion, following different pathways, to reach their specific destination. However the results have shown that the pathways used to reach its destinations overlapped. This would suggest that there is a possibility of the cells using the same pathway to move from the beginning production to the destination that is the adrenal medulla (for chromaffin cells) and the preaortic ganglion (other cells involved in the sympathetic system).

One particular study done by M.Yamato in 2004, along with his fellow scientists attempted to study the migration of neural crest cells in Wistar rats. In order to observe the formation adrenal medulla from the neural crest cells during the embryonic period, Yamato used anti - tyrosine hydroxylase (TH) antiserum injected into the rat embryos between 13-17 days of gestation. The anti - TH antiserum stain allows the scientists to visualize the neural crest cells under a light microscope. Later three dimensional images were created. From the images observed between 13 to 15 days of gestation, the TH - positive cells can be seen to move from the dorsal to the adrenal primordium{{#pmid:15240937|PMID15240937}}. After 16 days it was observed that a capsule had formed in some parts and TH - positive cells had penetrated the adrenal gland{{#pmid:15240937|PMID15240937}}. At seventeen days, TH - positive cells can be seen collecting at the medial part of the adrenal gland. The reconstructed images also shows that at the later stages during the 16-17 days of gestation, the accumulation of TH - positive cells grow and in combination with cell division leads to the formation of the adrenal medulla.

(Pubmed: 15240937)

=====Chicken models=====
Chicken and rat models are often the most commonly used models when dealing with neural crest cells. In this particular review, collates multiple researchers results and presents evidence to discuss previous information suggesting that sympathetic neurons and chromaffin cells do not share a common progenitor{{#pmid:3693940|PMID3693940}}. The relevant study involved the use of cell cultures, Sympathoadrneal (SA) progenitor cells from embryonic(from chick embryos) and eary developmental stages were able to be procured. From these cultures it was easy to identify that glucocorticoids were crucial in the differentiation of SA cells into their derivatives, sympathetic neurons and chromaffin cells.

Another study conducted deals with the role of the BMP-4 protein and its importance in the development of the adrenal medullary cells, chromaffin cells{{#pmid:18945349|PMID18945349}}. Previous research had shown that BMP - 4 a growth factor is plays an important role in the regulation of chromaffin cell production{{#pmid:10679774|PMID10679774}}. The researchers incubated chick embryos for 3 - 9 embryonic days and dissected them to be used for tissue cultures. First a in situ hybridisation study was conducted in order to find where

unedited

Cell culture studies using isolated SA progenitor cells from embryonic and early postnatal sympathetic ganglia and adrenal gland have suggested that glucocorticoids play a crucial role in the diversification of SA cells into sympathetic neurons and chromaffin cells [22-24]; for reviews see [2,5,6,25], by suppressing a neuronal differentiation programme in SA cells destined to become chromaffin cells. However, analysis of mice deficient for the glucocorticoid receptor [26] or lacking an adrenal cortex [27] revealed that chromaffin cell differentiation was largely unimpaired suggesting that cues unrelated to glucocorticoid receptor signalling and the adrenal cortex triggered the chromaffin phenotype. This notion was corroborated and extended by studies showing that chick SA progenitors are already heterogeneous in terms of neurofilament-M (NF-M) expression prior to populating the adrenal gland and sympathetic ganglia [28] with presumptive neuronal cells co-expressing tyrosine hydroxylase (TH) and NF-M, and presumptive neuroendocrine cells being TH-positive and NF-M-negative. This indicated that specification of the respective phenotypes occurred either during migration or even prior to migration at the level of the NT.

A recent study by Krispin et al. [7,29] showed that in the trunk NT of avian embryos, precursors for sympathetic ganglia, Schwann cells, sensory dorsal root ganglionic neurons, and melanocytes leave the NT in successive, largely non-overlapping waves, some being already distinct while still residing in the NT. Although adrenal chromaffin cells were not addressed in this study, the results raised the possibility that sympathetic neurons and chromaffin cells might also already be distinct at the level of the NT. We therefore conducted single cell electroporations (EPs) of green fluorescent protein (GFP)-DNA into pre-migratory NC cells at the level of somites 18–24 (“adrenomedullary level”), where both chromaffin cells and sympathetic neurons arise [30]. The timing and location of EPs was directed to label the earliest progenitors that undergo delamination, previously shown to generate the sympathetic lineage [7,29], and the progeny of labelled cells was then analysed at E6 following homing to their target areas. Our results indicate that in more than 80% of the cases the progeny of a single labelled cell ends up in both sympathetic ganglia and adrenal gland, being mostly NF-M-negative in the adrenal gland and NF-M-positive in sympathetic ganglia. This suggests that chromaffin cells and sympathetic neurons share a common progenitor in the NT and that diversification of the phenotypes occurs during migration or assembly in primary sympathetic ganglia at the dorsal aorta.
The sympathoadrenal (SA) cell lineage is a major sub-lineage of the NC that gives rise to sympathetic neurons, intra- and extra-adrenal chromaffin cells, and the small intensely fluorescent (SIF) cells, which are intermediate between sympathetic neurons and chromaffin cells [2-5]. SA derivatives share several features, including the ability to synthesize, store, and release catecholamines, but also exhibit traits specific for each cell type, such as axons, dendrites, and neurofilaments, which are only found in sympathetic neurons but not chromaffin cells.

3693940

Prenatal adrenal gland development has been described in numerous published reports covering a wide variety of species, including the ox (Katznelson, 1966; Wrobel and Suss, 1999), sheep (Davies, 1950; Wintour et al., 1975; Upadhyay and Zamboni, 1982; Naaman‐Reperant and Durand, 1997; Grino, 2004), swine (Sokolov et al., 2006) and mouse (Waring, 1935; Ikeda et al., 1994; Sass, 1996; Nyska and Maronpot, 1999; Bland et al., 2003; Val et al., 2007). Adrenal gland development also has been extensively described for humans as well (Kolliker, 1879; Minot, 1892; Zuckerkandl, 1912; Wieman, 1920; Ikeda et al., 1981; Langlois et al., 2002; Hanley and Arit, 2006).

https://www.sciencedirect.com/science/article/pii/S0925477302004550
http://dev.biologists.org/content/develop/126/13/2935.full.pdf

===Current research (labs)===
----

==== Sympathoadrenal neural crest cells====

As explained above the adrenal medulla plays an important part in the autonomic system of an adult human. The chromaffin cells, in particular, are important neural crest derived cell that is closely related to the adrenal medulla. Previous findings have focused specifically on the mechanisms controlling the NCC migration and how these cells go on to form the different derivatives in their particular destinations in the embryo. For example, as previously explained studies have shown that chromaffin cells have been observed to move to the adrenal gland to form the medulla of the adrenal gland.

The findings presented until now have focused on the mechanisms controlling migration along the dorsolateral path. In comparison, our understanding of the mechanisms controlling NCC migration along the ventral path are complicated by the fact that this population comprises multiple precursors that form different derivatives in distinct regions of the embryo. For example, ventrally migrating NCCs either stop within the sclerotome in close association with the neural tube to form neurons and glia of the sensory nervous system (i.e. the dorsal root ganglia [DRG]), while other NCCs continue to migrate further ventrally to form the autonomic nervous system (i.e. sympathetic ganglia and chromaffin cells of the adrenal gland)<ref>Lumb, R., & Schwarz, Q. (2015). Sympathoadrenal neural crest cells: The known, unknown and forgotten?. Development, Growth & Differentiation, 57(2), 146-157. doi: 10.1111/dgd.12189</ref>.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/dgd.12189

Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type.

The autonomic nervous system is very important in understanding the human body and in turn understanding health. This report goes through a recent study that involves the adrenal medullary cells, in particular chromaffin cells, and their potential to be used to model certain pathological diseases related to these cells. This is part of a study that also involves neural crest cells and their ability to differentiate into multiple different types of cells.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693940/

===Glossary===
----
===Reference list===

2018 Group Project 1

2018-10-15T04:01:41Z

Z5113627: /* Genes and Transcription Factors Involved with the Adrenal Medulla's Development */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===

----

The neural crest of an embryo differentiates and migrates to form various components of the body. One of these tissues is the medulla of the adrenal gland which is involved in the production of adrenalin and noradrenalin. This project will comprehensively outline the history of neural crest research, the embryonic developmental time course, tissue and organ structure, molecular mechanisms, abnormalities, animal models and current research.

===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.
[[File:NC Location.jpg|left|450px|thumb|The neural crest]]

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniably lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Embryonic origins===
----
[[File:Trunk_NCC_migration.jpg|left|450px|thumb|Trunk NCC migration]]
The adrenal gland is made up of the adrenal cortex and adrenal medulla, which both have different embryonic origins. The adrenal medulla arises from the neural crest tissue, found near the level of the coeliac plexus & sympathetic ganglion at somites 18-24 {{#pmid:16124976|PMID16124976}}. Specifically, this neural crest tissue comes from the trunk neural crest cells (see above figure to determine the approximate location in an embryo) <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
The trunk neural crest coordinates the development of the endocrine system, secretory cells, the peripheral nervous system and, to some degree, skeletal development, as well as innervation of the intestine {{#pmid: 28287247|PMID 28287247}}. The trunk neural cells arise caudally, undergo an epithelial to mesenchymal transition and follow three migratory pathways {{#pmid:20399766|PMID20399766}}.
[[File:Differentiation_of_NCC.jpg|left|580px|thumb|Differentiation of chromaffin cells]]
- A dorsolateral pathway (between ectoderm and somites), these become melanocytes, travel up to the point of the dermis and become a major part of the hair follicles and skin <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
- A ventrolateral pathway (through the somites)
- A ventromedial pathway (between neural tube and posterior schlerotome){{#pmid:20399766|PMID20399766}}.

Migration of neural crest cells from the sympathetic ganglion is what leads to the development of the adrenal medulla. In week 8 of development, immature cells called neuroblasts migrate through to the inner portion of the medulla, where they become the adrenal medulla {{#pmid:19683477|PMID19683477}}. Chromaffin cells are neuroendocrine cells and are found in the sympathetic ganglia and make up the majority of the adrenal medulla{{#pmid:19683477|PMID19683477}}. They synthesise and release a range of hormones in the body and arise from the temporary neural crest. The term chromaffin was inspired by the staining capacity of these cells when they came into contact with chrome salts. They make, store, export and use catecholamines, responsible for making noradrenaline and originate at the caudal region of somites 18-24 of the neural crest, also known as the adrenomedullary region {{#pmid:19683477|PMID19683477}}.

For cells to leave the neural crest and begin their migration, certain conditions need to be met, that is, the cells need to be loosely connected, their tight junctions becoming relaxed, initiated by "Slug protein" and a loss of N-Cadherin which also leads to the loosening of these junctions. The surrounding matrix as well as chemotactic and stem cell factors of the neural tube are then what dictates how the neural crest cells move, some proteins stopping their migration to that area and others encouraging the movement <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. After splitting apart, the first neural crest cells move ventrally and pass into the spaces between the somites and then, through the anterior portions of each segment until they arrive at the para-aortic sites, where they become the cells of the sympathetic ganglia and the adrenal medulla {{#pmid:19683477|PMID19683477}}. BMP-4 (bone morphogenetic protein 4) then acts on these neural crest cells, preventing them from becoming cells that have a neural function and causing them to become chromaffin cells at the adrenal medulla. Glucocorticoids then play a role in maintenance of chromaffin cells in postnatal life, this was only found recently, as previously it was thought that glucocorticoids were responsible entirely for the differentiation of neural crest cells into chromaffin, or adrenomedullary cells {{#pmid:23220335|PMID23220335}}.

===Developmental/adult function===
----
====Normal Structure and Function of the Adrenal Medulla====

The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The medulla contains secretory cells called chromaffin cells, due to the agents they produce when oxidised, such as chromate. These cells secrete epinephrine and norepinephrine in response to various substances such as acetylcholine.

There are three types of cells in the adult adrenal medulla:

* Epinephrine cells
* Norepinephrine cells
* Small granule-containing cells (SGCs)

These cells also produce various other peptides such as substance P and neurotensin. The adrenal medulla also contains presynaptic sympathetic ganglion cells. {{#pmid:1694230|PMID1694230}}

These cells have unique neuroendocrine characteristics as a result of their neural-crest origin. They receive preganglionic innervation by thoracic splanchnic nerves, and could almost be considered a specialised sympathetic ganglion. With postganglgionic bodies, cells of the medulla are densely clustered around their vasculature for the secretion of hormones into the bloodstream to moderate the concentration of epinephrine and norepinephrine.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus. {{#pmid:11215683|PMID11215683}} [[File:Dd.jpg|400px|thumb|right|Adult Adrenal Glands in situ]]

====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses. {{#pmid:19396395|PMID19396395}}

----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

The Adrenal Medulla's neural crest tissue begins at the process of neurulation, the formation of the neural tube from the folding neural plate. It is here that several key chemical players are at work. The classic interpretation of Sonic Hedgehog (Shh) and Wnt signalling pathways as the only mediators here, has been shown to be incorrect. Research has uncovered other signallers such as:

*Bone-Morphogenic-Protein-4 (BMP4) for the regional expression of nervous system distinctions in the growing neural plate. This maintains two important embryonic trancription factors known as Paired-Box (PAX) Genes 3 and 7 which can allow for expression of neural crest markers HNK-1, SRY-Box (SOX) 8, 9 and 10 as the neural tube closes and the neural crest delaminates from the folding.

*Slug via

The importance of Somitogenesis and Neural Crest come to a head when neural crest cells must migrate anteriorly past somites 18 to 24

Members of the SOX gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

[[File:Catecholamine_Synthesis.jpg|400px|thumb|right|Biochemical Cascade of Catecholamine Synthesis]]

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands.

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291442/
https://www.ncbi.nlm.nih.gov/pubmed/19396395

===Abnormalities/abnormal development===
----

Abnormalities of the Adrenal Medulla are much less common than its mesoderm-derived shell of the Adrenal Gland. Three of the most notorious abnormalities of the Adrenal Medulla include:

* Pheochromocytomas
* Ganglioneuromas
* Neuroblastomas

Pheochromocytomas-

Ganglioneuromas-

Neuroblastomas-

Apart from these abnormalities, there are other pathologies that may be connected to the adrenal medulla. One such example is a pathology of the Organ of Zuckerkandl. Also known as the para-aortic body, the Organ of Zuckerkandl is a primarily-gestational organ comprised of chromaffin cells.

===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

====Chromaffin cells====
There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells{{#pmid:19377845|PMID19377845}}. The neural crest cells give rise to chromaffin cells of the adrenal medulla.

=====Rat Models=====
Previous research has reported that nueral crest cells differentiate into chromaffin cells around 19 days of gestation before forming the adrenal medulla{{#pmid:28684471|PMID2868441}}. Past research had also suggested that neural crest derived adrenal gland cells migrate using the sympathetic ganglia to the adrenal gland or preaortic ganglion, following different pathways, to reach their specific destination. However the results have shown that the pathways used to reach its destinations overlapped. This would suggest that there is a possibility of the cells using the same pathway to move from the beginning production to the destination that is the adrenal medulla (for chromaffin cells) and the preaortic ganglion (other cells involved in the sympathetic system).

One particular study done by M.Yamato in 2004, along with his fellow scientists attempted to study the migration of neural crest cells in Wistar rats. In order to observe the formation adrenal medulla from the neural crest cells during the embryonic period, Yamato used anti - tyrosine hydroxylase (TH) antiserum injected into the rat embryos between 13-17 days of gestation. The anti - TH antiserum stain allows the scientists to visualize the neural crest cells under a light microscope. Later three dimensional images were created. From the images observed between 13 to 15 days of gestation, the TH - positive cells can be seen to move from the dorsal to the adrenal primordium{{#pmid:15240937|PMID15240937}}. After 16 days it was observed that a capsule had formed in some parts and TH - positive cells had penetrated the adrenal gland{{#pmid:15240937|PMID15240937}}. At seventeen days, TH - positive cells can be seen collecting at the medial part of the adrenal gland. The reconstructed images also shows that at the later stages during the 16-17 days of gestation, the accumulation of TH - positive cells grow and in combination with cell division leads to the formation of the adrenal medulla.

(Pubmed: 15240937)

=====Chicken models=====
Chicken and rat models are often the most commonly used models when dealing with neural crest cells. In this particular report, the focus was also regarding the validity of previous research suggesting that sympathetic neurons and chromaffin cells do not share a common progenitor{{#pmid:3693940|PMID3693940}}. The researchers used cell cultures, Sympathoadrneal (SA) progenitor cells from embryonic(from chick embryos) and eary developmental stages were able to be procured. From these cultures it was easy to identify that glucocorticoids were crucial in the differentiation of SA cells into their derivatives, sympathetic neurons and chromaffin cells.

unedited

Cell culture studies using isolated SA progenitor cells from embryonic and early postnatal sympathetic ganglia and adrenal gland have suggested that glucocorticoids play a crucial role in the diversification of SA cells into sympathetic neurons and chromaffin cells [22-24]; for reviews see [2,5,6,25], by suppressing a neuronal differentiation programme in SA cells destined to become chromaffin cells. However, analysis of mice deficient for the glucocorticoid receptor [26] or lacking an adrenal cortex [27] revealed that chromaffin cell differentiation was largely unimpaired suggesting that cues unrelated to glucocorticoid receptor signalling and the adrenal cortex triggered the chromaffin phenotype. This notion was corroborated and extended by studies showing that chick SA progenitors are already heterogeneous in terms of neurofilament-M (NF-M) expression prior to populating the adrenal gland and sympathetic ganglia [28] with presumptive neuronal cells co-expressing tyrosine hydroxylase (TH) and NF-M, and presumptive neuroendocrine cells being TH-positive and NF-M-negative. This indicated that specification of the respective phenotypes occurred either during migration or even prior to migration at the level of the NT.

A recent study by Krispin et al. [7,29] showed that in the trunk NT of avian embryos, precursors for sympathetic ganglia, Schwann cells, sensory dorsal root ganglionic neurons, and melanocytes leave the NT in successive, largely non-overlapping waves, some being already distinct while still residing in the NT. Although adrenal chromaffin cells were not addressed in this study, the results raised the possibility that sympathetic neurons and chromaffin cells might also already be distinct at the level of the NT. We therefore conducted single cell electroporations (EPs) of green fluorescent protein (GFP)-DNA into pre-migratory NC cells at the level of somites 18–24 (“adrenomedullary level”), where both chromaffin cells and sympathetic neurons arise [30]. The timing and location of EPs was directed to label the earliest progenitors that undergo delamination, previously shown to generate the sympathetic lineage [7,29], and the progeny of labelled cells was then analysed at E6 following homing to their target areas. Our results indicate that in more than 80% of the cases the progeny of a single labelled cell ends up in both sympathetic ganglia and adrenal gland, being mostly NF-M-negative in the adrenal gland and NF-M-positive in sympathetic ganglia. This suggests that chromaffin cells and sympathetic neurons share a common progenitor in the NT and that diversification of the phenotypes occurs during migration or assembly in primary sympathetic ganglia at the dorsal aorta.
The sympathoadrenal (SA) cell lineage is a major sub-lineage of the NC that gives rise to sympathetic neurons, intra- and extra-adrenal chromaffin cells, and the small intensely fluorescent (SIF) cells, which are intermediate between sympathetic neurons and chromaffin cells [2-5]. SA derivatives share several features, including the ability to synthesize, store, and release catecholamines, but also exhibit traits specific for each cell type, such as axons, dendrites, and neurofilaments, which are only found in sympathetic neurons but not chromaffin cells.

3693940

Prenatal adrenal gland development has been described in numerous published reports covering a wide variety of species, including the ox (Katznelson, 1966; Wrobel and Suss, 1999), sheep (Davies, 1950; Wintour et al., 1975; Upadhyay and Zamboni, 1982; Naaman‐Reperant and Durand, 1997; Grino, 2004), swine (Sokolov et al., 2006) and mouse (Waring, 1935; Ikeda et al., 1994; Sass, 1996; Nyska and Maronpot, 1999; Bland et al., 2003; Val et al., 2007). Adrenal gland development also has been extensively described for humans as well (Kolliker, 1879; Minot, 1892; Zuckerkandl, 1912; Wieman, 1920; Ikeda et al., 1981; Langlois et al., 2002; Hanley and Arit, 2006).

https://www.sciencedirect.com/science/article/pii/S0925477302004550
http://dev.biologists.org/content/develop/126/13/2935.full.pdf

===Current research (labs)===
----

==== Sympathoadrenal neural crest cells====

As explained above the adrenal medulla plays an important part in the autonomic system of an adult human. The chromaffin cells, in particular, are important neural crest derived cell that is closely related to the adrenal medulla. Previous findings have focused specifically on the mechanisms controlling the NCC migration and how these cells go on to form the different derivatives in their particular destinations in the embryo. For example, as previously explained studies have shown that chromaffin cells have been observed to move to the adrenal gland to form the medulla of the adrenal gland.

The findings presented until now have focused on the mechanisms controlling migration along the dorsolateral path. In comparison, our understanding of the mechanisms controlling NCC migration along the ventral path are complicated by the fact that this population comprises multiple precursors that form different derivatives in distinct regions of the embryo. For example, ventrally migrating NCCs either stop within the sclerotome in close association with the neural tube to form neurons and glia of the sensory nervous system (i.e. the dorsal root ganglia [DRG]), while other NCCs continue to migrate further ventrally to form the autonomic nervous system (i.e. sympathetic ganglia and chromaffin cells of the adrenal gland)

<ref>https://onlinelibrary.wiley.com/doi/pdf/10.1111/dgd.12189</ref>

https://onlinelibrary.wiley.com/doi/pdf/10.1111/dgd.12189

Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type.

The autonomic nervous system is very important in understanding the human body and in turn understanding health. This report goes through a recent study that involves the adrenal medullary cells, in particular chromaffin cells, and their potential to be used to model certain pathological diseases related to these cells. This is part of a study that also involves neural crest cells and their ability to differentiate into multiple different types of cells.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693940/

===Glossary===
----
===Reference list===

2018 Group Project 1

2018-10-14T10:30:29Z

Z5113627: /* Genes and Transcription Factors Involved with the Adrenal Medulla's Development */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===
[[User:Z5014972|Z5014972]] ([[User talk:Z5014972|talk]]) 12:47, 14 August 2018 (AEST)z5014972
good review article https://link.springer.com/article/10.1007%2Fs12022-009-9070-6
----

The neural crest of an embryo differentiates and migrates to form various components of the body. One of these tissues is the medulla of the adrenal gland which is involved in the production of adrenalin and noradrenalin. This project will comprehensively outline the history of neural crest research, the embryonic developmental time course, tissue and organ structure, molecular mechanisms, abnormalities, animal models and current research.

===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.
[[File:NC Location.jpg|left|450px|thumb|The neural crest]]

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniably lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Embryonic origins===
----
[[File:Trunk_NCC_migration.jpg|left|450px|thumb|Trunk NCC migration]]
The adrenal gland is made up of the adrenal cortex and adrenal medulla, which both have different embryonic origins. The adrenal medulla arises from the neural crest tissue, found near the level of the coeliac plexus & sympathetic ganglion at somites 18-24 {{#pmid:16124976|PMID16124976}}. Specifically, this neural crest tissue comes from the trunk neural crest cells (see above figure to determine the approximate location in an embryo) <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
The trunk neural crest coordinates the development of the endocrine system, secretory cells, the peripheral nervous system and, to some degree, skeletal development, as well as innervation of the intestine {{#pmid: 28287247|PMID 28287247}}. The trunk neural cells arise caudally, undergo an epithelial to mesenchymal transition and follow three migratory pathways {{#pmid:20399766|PMID20399766}}.
[[File:Differentiation_of_NCC.jpg|left|580px|thumb|Differentiation of chromaffin cells]]
- A dorsolateral pathway (between ectoderm and somites), these become melanocytes, travel up to the point of the dermis and become a major part of the hair follicles and skin <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
- A ventrolateral pathway (through the somites)
- A ventromedial pathway (between neural tube and posterior schlerotome){{#pmid:20399766|PMID20399766}}.

Migration of neural crest cells from the sympathetic ganglion is what leads to the development of the adrenal medulla. In week 8 of development, immature cells called neuroblasts migrate through to the inner portion of the medulla, where they become the adrenal medulla {{#pmid:19683477|PMID19683477}}. Chromaffin cells are neuroendocrine cells and are found in the sympathetic ganglia and make up the majority of the adrenal medulla{{#pmid:19683477|PMID19683477}}. They synthesise and release a range of hormones in the body and arise from the temporary neural crest. The term chromaffin was inspired by the staining capacity of these cells when they came into contact with chrome salts. They make, store, export and use catecholamines, responsible for making noradrenaline and originate at the caudal region of somites 18-24 of the neural crest, also known as the adrenomedullary region {{#pmid:19683477|PMID19683477}}.

For cells to leave the neural crest and begin their migration, certain conditions need to be met, that is, the cells need to be loosely connected, their tight junctions becoming relaxed, initiated by "Slug protein" and a loss of N-Cadherin which also leads to the loosening of these junctions. The surrounding matrix as well as chemotactic and stem cell factors of the neural tube are then what dictates how the neural crest cells move, some proteins stopping their migration to that area and others encouraging the movement <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. After splitting apart, the first neural crest cells move ventrally and pass into the spaces between the somites and then, through the anterior portions of each segment until they arrive at the para-aortic sites, where they become the cells of the sympathetic ganglia and the adrenal medulla {{#pmid:19683477|PMID19683477}}. BMP-4 (bone morphogenetic protein 4) then acts on these neural crest cells, preventing them from becoming cells that have a neural function and causing them to become chromaffin cells at the adrenal medulla. Glucocorticoids then play a role in maintenance of chromaffin cells in postnatal life, this was only found recently, as previously it was thought that glucocorticoids were responsible entirely for the differentiation of neural crest cells into chromaffin, or adrenomedullary cells {{#pmid:23220335|PMID23220335}}.

===Developmental/adult function===
----
====Normal Structure and Function of the Adrenal Medulla====

The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The medulla contains secretory cells called chromaffin cells, due to the agents they produce when oxidised, such as chromate. These cells secrete epinephrine and norepinephrine in response to various substances such as acetylcholine.

There are three types of cells in the adult adrenal medulla:

* Epinephrine cells
* Norepinephrine cells
* Small granule-containing cells (SGCs)

These cells also produce various other peptides such as substance P and neurotensin. The adrenal medulla also contains presynaptic sympathetic ganglion cells. {{#pmid:1694230|PMID1694230}}

These cells have unique neuroendocrine characteristics as a result of their neural-crest origin. They receive preganglionic innervation by thoracic splanchnic nerves, and could almost be considered a specialised sympathetic ganglion. With postganglgionic bodies, cells of the medulla are densely clustered around their vasculature for the secretion of hormones into the bloodstream to moderate the concentration of epinephrine and norepinephrine.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus. {{#pmid:11215683|PMID11215683}} [[File:Dd.jpg|400px|thumb|right|Adult Adrenal Glands in situ]]

====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses. {{#pmid:19396395|PMID19396395}}

----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

The Adrenal Medulla's neural crest tissue begins at the process of neurulation, the formation of the neural tube from the folding neural plate. It is here that several key chemical players are at work. The classic interpretation of Sonic Hedgehog (Shh) and Wnt signalling pathways as the only mediators here, has been shown to be incorrect. Research has uncovered other signallers such as:

*Bone-Morphogenic-Protein-4 (BMP4)

The importance of Somitogenesis and Neural Crest come to a head when neural crest cells must migrate anteriorly past somites 18 to 24

Members of the SOX (SRY-Box) gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

[[File:Catecholamine_Synthesis.jpg|400px|thumb|right|Biochemical Cascade of Catecholamine Synthesis]]

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands.

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291442/
https://www.ncbi.nlm.nih.gov/pubmed/19396395

===Abnormalities/abnormal development===
----

Abnormalities of the Adrenal Medulla are much less common than its mesoderm-derived shell of the Adrenal Gland. Three of the most notorious abnormalities of the Adrenal Medulla include:

* Pheochromocytomas
* Ganglioneuromas
* Neuroblastomas

Pheochromocytomas-

Ganglioneuromas-

Neuroblastomas-

Apart from these abnormalities, there are other pathologies that may be connected to the adrenal medulla. One such example is a pathology of the Organ of Zuckerkandl. Also known as the para-aortic body, the Organ of Zuckerkandl is a primarily-gestational organ comprised of chromaffin cells.

===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

====Chromaffin cells====
There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells. The neural crest cells give rise to chromaffin cells of the adrenal medulla.

=====Rat Models=====
Previous research has reported that nueral crest cells differentiate into chromaffin cells around 19 days of gestation before forming the adrenal medulla{{#pmid:28684471|PMID2868441}}. Past research had also suggested that neural crest derived adrenal gland cells migrate using the sympathetic ganglia to the adrenal gland or preaortic ganglion, following different pathways, to reach their specific destination. However the results have shown that the pathways used to reach its destinations overlapped. This would suggest that there is a possibility of the cells using the same pathway to move from the beginning production to the destination that is the adrenal medulla (for chromaffin cells) and the preaortic ganglion (other cells involved in the sympathetic system).

One particular study done by M.Yamato in 2004, along with his fellow scientists attempted to study the migration of neural crest cells in Wistar rats. In order to observe the formation adrenal medulla from the neural crest cells during the embryonic period, Yamato used anti - tyrosine hydroxylase (TH) antiserum injected into the rat embryos between 13-17 days of gestation. The anti - TH antiserum stain allows the scientists to visualize the neural crest cells under a light microscope. Later three dimensional images were created. From the images observed between 13 to 15 days of gestation, the TH - positive cells can be seen to move from the dorsal to the adrenal primordium{{#pmid:15240937|PMID15240937}}. After 16 days it was observed that a capsule had formed in some parts and TH - positive cells had penetrated the adrenal gland{{#pmid:15240937|PMID15240937}}. At seventeen days, TH - positive cells can be seen collecting at the medial part of the adrenal gland. The reconstructed images also shows that at the later stages during the 16-17 days of gestation, the accumulation of TH - positive cells grow and in combination with cell division leads to the formation of the adrenal medulla.

(Pubmed: 15240937)

=====Chicken models=====
Chicken and rat models are often the most commonly used models when dealing with neural crest cells. In this particular report, the focus was also regarding the validity of previous research suggesting that sympathetic neurons and chromaffin cells do not share a common progenitor{{#pmid:3693940|PMID3693940}}. The researchers used cell cultures, Sympathoadrneal (SA) progenitor cells from embryonic(from chick embryos) and eary developmental stages were able to be procured. From these cultures it was easy to identify that glucocorticoids were crucial in the differentiation of SA cells into their derivatives, sympathetic neurons and chromaffin cells.

unedited

Cell culture studies using isolated SA progenitor cells from embryonic and early postnatal sympathetic ganglia and adrenal gland have suggested that glucocorticoids play a crucial role in the diversification of SA cells into sympathetic neurons and chromaffin cells [22-24]; for reviews see [2,5,6,25], by suppressing a neuronal differentiation programme in SA cells destined to become chromaffin cells. However, analysis of mice deficient for the glucocorticoid receptor [26] or lacking an adrenal cortex [27] revealed that chromaffin cell differentiation was largely unimpaired suggesting that cues unrelated to glucocorticoid receptor signalling and the adrenal cortex triggered the chromaffin phenotype. This notion was corroborated and extended by studies showing that chick SA progenitors are already heterogeneous in terms of neurofilament-M (NF-M) expression prior to populating the adrenal gland and sympathetic ganglia [28] with presumptive neuronal cells co-expressing tyrosine hydroxylase (TH) and NF-M, and presumptive neuroendocrine cells being TH-positive and NF-M-negative. This indicated that specification of the respective phenotypes occurred either during migration or even prior to migration at the level of the NT.

A recent study by Krispin et al. [7,29] showed that in the trunk NT of avian embryos, precursors for sympathetic ganglia, Schwann cells, sensory dorsal root ganglionic neurons, and melanocytes leave the NT in successive, largely non-overlapping waves, some being already distinct while still residing in the NT. Although adrenal chromaffin cells were not addressed in this study, the results raised the possibility that sympathetic neurons and chromaffin cells might also already be distinct at the level of the NT. We therefore conducted single cell electroporations (EPs) of green fluorescent protein (GFP)-DNA into pre-migratory NC cells at the level of somites 18–24 (“adrenomedullary level”), where both chromaffin cells and sympathetic neurons arise [30]. The timing and location of EPs was directed to label the earliest progenitors that undergo delamination, previously shown to generate the sympathetic lineage [7,29], and the progeny of labelled cells was then analysed at E6 following homing to their target areas. Our results indicate that in more than 80% of the cases the progeny of a single labelled cell ends up in both sympathetic ganglia and adrenal gland, being mostly NF-M-negative in the adrenal gland and NF-M-positive in sympathetic ganglia. This suggests that chromaffin cells and sympathetic neurons share a common progenitor in the NT and that diversification of the phenotypes occurs during migration or assembly in primary sympathetic ganglia at the dorsal aorta.
The sympathoadrenal (SA) cell lineage is a major sub-lineage of the NC that gives rise to sympathetic neurons, intra- and extra-adrenal chromaffin cells, and the small intensely fluorescent (SIF) cells, which are intermediate between sympathetic neurons and chromaffin cells [2-5]. SA derivatives share several features, including the ability to synthesize, store, and release catecholamines, but also exhibit traits specific for each cell type, such as axons, dendrites, and neurofilaments, which are only found in sympathetic neurons but not chromaffin cells.

3693940

Prenatal adrenal gland development has been described in numerous published reports covering a wide variety of species, including the ox (Katznelson, 1966; Wrobel and Suss, 1999), sheep (Davies, 1950; Wintour et al., 1975; Upadhyay and Zamboni, 1982; Naaman‐Reperant and Durand, 1997; Grino, 2004), swine (Sokolov et al., 2006) and mouse (Waring, 1935; Ikeda et al., 1994; Sass, 1996; Nyska and Maronpot, 1999; Bland et al., 2003; Val et al., 2007). Adrenal gland development also has been extensively described for humans as well (Kolliker, 1879; Minot, 1892; Zuckerkandl, 1912; Wieman, 1920; Ikeda et al., 1981; Langlois et al., 2002; Hanley and Arit, 2006).

https://www.sciencedirect.com/science/article/pii/S0925477302004550
http://dev.biologists.org/content/develop/126/13/2935.full.pdf

===Current research (labs)===
----
As explained above the adrenal medulla plays an important part in the autonomic system of an adult human. The chromaffin cells, in particular, are important neural crest derived cell that is closely related to the adrenal medulla. Previous findings have focused specifically on the mechanisms controlling the NCC migration and how these cells go on to form the different derivatives in their particular destinations in the embryo. For example, as previously explained studies have shown that chromaffin cells have been observed to move to the adrenal gland to form the medulla of the adrenal gland.

The findings presented until now have focused on the mechanisms controlling migration along the dorsolateral path. In comparison, our understanding of the mechanisms controlling NCC migration along the ventral path are complicated by the fact that this population comprises multiple precursors that form different derivatives in distinct regions of the embryo. For example, ventrally migrating NCCs either stop within the sclerotome in close association with the neural tube to form neurons and glia of the sensory nervous system (i.e. the dorsal root ganglia [DRG]), while other NCCs continue to migrate further ventrally to form the autonomic nervous system (i.e. sympathetic ganglia and chromaffin cells of the adrenal gland)

<ref>https://onlinelibrary.wiley.com/doi/pdf/10.1111/dgd.12189</ref>

https://onlinelibrary.wiley.com/doi/pdf/10.1111/dgd.12189

Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type.

The autonomic nervous system is very important in understanding the human body and in turn understanding health. This report goes through a recent study that involves the adrenal medullary cells, in particular chromaffin cells, and their potential to be used to model certain pathological diseases related to these cells. This is part of a study that also involves neural crest cells and their ability to differentiate into multiple different types of cells.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693940/

===Glossary===
----
===Reference list===

2018 Group Project 1

2018-10-14T07:51:12Z

Z5113627: /* Molecular mechanisms/factors/genes */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===
[[User:Z5014972|Z5014972]] ([[User talk:Z5014972|talk]]) 12:47, 14 August 2018 (AEST)z5014972
good review article https://link.springer.com/article/10.1007%2Fs12022-009-9070-6
----

The neural crest of an embryo differentiates and migrates to form various components of the body. One of these tissues is the medulla of the adrenal gland which is involved in the production of adrenalin and noradrenalin. This project will comprehensively outline the history of neural crest research, the embryonic developmental time course, tissue and organ structure, molecular mechanisms, abnormalities, animal models and current research.

===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.
[[File:NC Location.jpg|left|450px|thumb|The neural crest]]

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniably lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Embryonic origins===
----
[[File:Trunk_NCC_migration.jpg|left|450px|thumb|Trunk NCC migration]]
The adrenal gland is made up of the adrenal cortex and adrenal medulla, which both have different embryonic origins. The adrenal medulla arises from the neural crest tissue, found near the level of the coeliac plexus & sympathetic ganglion at somites 18-24 {{#pmid:16124976|PMID16124976}}. Specifically, this neural crest tissue comes from the trunk neural crest cells (see above figure to determine the approximate location in an embryo) <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
The trunk neural crest coordinates the development of the endocrine system, secretory cells, the peripheral nervous system and, to some degree, skeletal development, as well as innervation of the intestine {{#pmid: 28287247|PMID 28287247}}. The trunk neural cells arise caudally, undergo an epithelial to mesenchymal transition and follow three migratory pathways {{#pmid:20399766|PMID20399766}}.
[[File:Differentiation_of_NCC.jpg|left|580px|thumb|Differentiation of chromaffin cells]]
- A dorsolateral pathway (between ectoderm and somites), these become melanocytes, travel up to the point of the dermis and become a major part of the hair follicles and skin <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
- A ventrolateral pathway (through the somites)
- A ventromedial pathway (between neural tube and posterior schlerotome){{#pmid:20399766|PMID20399766}}.

Migration of neural crest cells from the sympathetic ganglion is what leads to the development of the adrenal medulla. In week 8 of development, immature cells called neuroblasts migrate through to the inner portion of the medulla, where they become the adrenal medulla {{#pmid:19683477|PMID19683477}}. Chromaffin cells are neuroendocrine cells and are found in the sympathetic ganglia and make up the majority of the adrenal medulla{{#pmid:19683477|PMID19683477}}. They synthesise and release a range of hormones in the body and arise from the temporary neural crest. The term chromaffin was inspired by the staining capacity of these cells when they came into contact with chrome salts. They make, store, export and use catecholamines, responsible for making noradrenaline and originate at the caudal region of somites 18-24 of the neural crest, also known as the adrenomedullary region {{#pmid:19683477|PMID19683477}}.

For cells to leave the neural crest and begin their migration, certain conditions need to be met, that is, the cells need to be loosely connected, their tight junctions becoming relaxed, initiated by "Slug protein" and a loss of N-Cadherin which also leads to the loosening of these junctions. The surrounding matrix as well as chemotactic and stem cell factors of the neural tube are then what dictates how the neural crest cells move, some proteins stopping their migration to that area and others encouraging the movement <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. After splitting apart, the first neural crest cells move ventrally and pass into the spaces between the somites and then, through the anterior portions of each segment until they arrive at the para-aortic sites, where they become the cells of the sympathetic ganglia and the adrenal medulla {{#pmid:19683477|PMID19683477}}. BMP-4 (bone morphogenetic protein 4) then acts on these neural crest cells, preventing them from becoming cells that have a neural function and causing them to become chromaffin cells at the adrenal medulla. Glucocorticoids then play a role in maintenance of chromaffin cells in postnatal life, this was only found recently, as previously it was thought that glucocorticoids were responsible entirely for the differentiation of neural crest cells into chromaffin, or adrenomedullary cells {{#pmid:23220335|PMID23220335}}.

===Developmental/adult function===
----
====Normal Structure and Function of the Adrenal Medulla====

The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The medulla contains secretory cells called chromaffin cells, due to the agents they produce when oxidised, such as chromate. These cells secrete epinephrine and norepinephrine in response to various substances such as acetylcholine.

There are three types of cells in the adult adrenal medulla:

* Epinephrine cells
* Norepinephrine cells
* Small granule-containing cells (SGCs)

These cells also produce various other peptides such as substance P and neurotensin. The adrenal medulla also contains presynaptic sympathetic ganglion cells. {{#pmid:1694230|PMID1694230}}

These cells have unique neuroendocrine characteristics as a result of their neural-crest origin. They receive preganglionic innervation by thoracic splanchnic nerves, and could almost be considered a specialised sympathetic ganglion. With postganglgionic bodies, cells of the medulla are densely clustered around their vasculature for the secretion of hormones into the bloodstream to moderate the concentration of epinephrine and norepinephrine.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus. {{#pmid:11215683|PMID11215683}} [[File:Dd.jpg|400px|thumb|right|Adult Adrenal Glands in situ]]

====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses. {{#pmid:19396395|PMID19396395}}

----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

The Adrenal Medulla's neural crest tissue begins at the process of neurulation, the formation of the neural tube from the folding neural plate. It is here that several key chemical players are at work. The classic interpretation of Sonic Hedgehog (Shh) and Wnt signalling pathways as the only mediators here, has been shown to be incorrect.

The importance of Somitogenesis and Neural Crest come to a head when neural crest cells must migrate anteriorly past somites 18 to 24

Members of the SOX (SRY-Box) gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

[[File:Catecholamine_Synthesis.jpg|400px|thumb|right|Biochemical Cascade of Catecholamine Synthesis]]

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands.

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291442/
https://www.ncbi.nlm.nih.gov/pubmed/19396395

===Abnormalities/abnormal development===
----

Abnormalities of the Adrenal Medulla are much less common than its mesoderm-derived shell of the Adrenal Gland. Three of the most notorious abnormalities of the Adrenal Medulla include:

* Pheochromocytomas
* Ganglioneuromas
* Neuroblastomas

Pheochromocytomas-

Ganglioneuromas-

Neuroblastomas-

Apart from these abnormalities, there are other pathologies that may be connected to the adrenal medulla. One such example is a pathology of the Organ of Zuckerkandl. Also known as the para-aortic body, the Organ of Zuckerkandl is a primarily-gestational organ comprised of chromaffin cells.

===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

====Chromaffin cells (in rat models)====
There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells. The neural crest cells give rise to chromaffin cells of the adrenal medulla.

Previous research has reported that nueral crest cells differentiate into chromaffin cells around 19 days of gestation before forming the adrenal medulla{{#pmid:28684471|PMID2868441}}. Past research had also suggested that neural crest derived adrenal gland cells migrate using the sympathetic ganglia to the adrenal gland or preaortic ganglion, following different pathways, to reach their specific destination. However the results have shown that the pathways used to reach its destinations overlapped. This would suggest that there is a possibility of the cells using the same pathway to move from the beginning production to the destination that is the adrenal medulla (for chromaffin cells) and the preaortic ganglion (other cells involved in the sympathetic system).

One particular study done by M.Yamato in 2004, along with his fellow scientists attempted to study the migration of neural crest cells in Wistar rats. In order to observe the formation adrenal medulla from the neural crest cells during the embryonic period, Yamato used anti - tyrosine hydroxylase (TH) antiserum injected into the rat embryos between 13-17 days of gestation. The anti - TH antiserum stain allows the scientists to visualize the neural crest cells under a light microscope. Later three dimensional images were created. From the images observed between 13 to 15 days of gestation, the TH - positive cells can be seen to move from the dorsal to the adrenal primordium{{#pmid:15240937|PMID15240937}}. After 16 days it was observed that a capsule had formed in some parts and TH - positive cells had penetrated the adrenal gland{{#pmid:15240937|PMID15240937}}. At seventeen days, TH - positive cells can be seen collecting at the medial part of the adrenal gland. The reconstructed images also shows that at the later stages during the 16-17 days of gestation, the accumulation of TH - positive cells grow and in combination with cell division leads to the formation of the adrenal medulla.

(Pubmed: 15240937)

Unedited

The finding that the line of TH - positive cells toward the adrenal gland almost disappeared at 17 days of gestation in the reconstructed image suggests that the migration of neural crest - derived cells to the adrenal gland is complete by the 17 days of gestation, after which the formation of the adrenal medulla is completed by cell division in the adrenal gland
Since TH is used in this study as an indicator of chromaffin cells (adrenal medullary cells) is an enzyme involved in the early stage of the synthetic pathway of adrenaline and noradrenaline, the TH - positive cells observed in this study may include not only chromaffin cells but also sympathetic ganglion cells and SIF cells.
It was previously thught that when neural crest - derived cells migrated via the sympatheti chain gangli into the adrenal gland or preaortic ganglion, they took different pathways to the respective destination at the time of passage through the ganglia of the sympathetic trunk.
However, the reconstructed images in this study showed that the pathway of neural crest - deriveed cells from the ganglia of the sympathetic trunk to the adrenal medulla overlapped with the pathway to the preaortic ganglion. We speculate that neural crest cells use the same pathway to migrate to the ganglia of the sympathetic trunk, to the adrenal gland, and to the preaortic ganglion, this onclusion is good agreement of the suggestion by Ahoren.
Ahonen suggested that some neural crest cells continue migration from the chain ganglia to the lateral sides of aorta, where they form the perirenal ganglia and adrenal medulla, and finally to the ventral side of the aorta to form the preaortic sympathetic tissue. However, that report only showed the several transverse sections of the fetal trunk for the a demonstration of the migration route of neural crest cells. In this study, using three dimensional reconstructed images, we aimed to observe how TH-labeled chromaffin cells penetrate into the adrenal anlage to form the adrenal medulla and whether the migration route of TH - positive cells from the adrenal connects the preaortic sympathetic ganglia
(M.Yamato, R. Yanai, K. Arishima, 2004)

Prenatal adrenal gland development has been described in numerous published reports covering a wide variety of species, including the ox (Katznelson, 1966; Wrobel and Suss, 1999), sheep (Davies, 1950; Wintour et al., 1975; Upadhyay and Zamboni, 1982; Naaman‐Reperant and Durand, 1997; Grino, 2004), swine (Sokolov et al., 2006) and mouse (Waring, 1935; Ikeda et al., 1994; Sass, 1996; Nyska and Maronpot, 1999; Bland et al., 2003; Val et al., 2007). Adrenal gland development also has been extensively described for humans as well (Kolliker, 1879; Minot, 1892; Zuckerkandl, 1912; Wieman, 1920; Ikeda et al., 1981; Langlois et al., 2002; Hanley and Arit, 2006).

https://www.sciencedirect.com/science/article/pii/S0925477302004550
http://dev.biologists.org/content/develop/126/13/2935.full.pdf

===Current research (labs)===
----
As explained above the adrenal medulla plays an important part in the autonomic system of an adult human. The chromaffin cells, in particular, are important neural crest derived cell that is closely related to the adrenal medulla. Previous findings have focused specifically on the mechanisms controlling the NCC migration and how these cells go on to form the different derivatives in their particular destinations in the embryo. For example, as previously explained studies have shown that chromaffin cells have been observed to move to the adrenal gland to form the medulla of the adrenal gland.

The findings presented until now have focused on the mechanisms controlling migration along the dorsolateral path. In comparison, our understanding of the mechanisms controlling NCC migration along the ventral path are complicated by the fact that this population comprises multiple precursors that form different derivatives in distinct regions of the embryo. For example, ventrally migrating NCCs either stop within the sclerotome in close association with the neural tube to form neurons and glia of the sensory nervous system (i.e. the dorsal root ganglia [DRG]), while other NCCs continue to migrate further ventrally to form the autonomic nervous system (i.e. sympathetic ganglia and chromaffin cells of the adrenal gland)

<ref>https://onlinelibrary.wiley.com/doi/pdf/10.1111/dgd.12189</ref>

https://onlinelibrary.wiley.com/doi/pdf/10.1111/dgd.12189

Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type.

The autonomic nervous system is very important in understanding the human body and in turn understanding health. This report goes through a recent study that involves the adrenal medullary cells, in particular chromaffin cells, and their potential to be used to model certain pathological diseases related to these cells. This is part of a study that also involves neural crest cells and their ability to differentiate into multiple different types of cells.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693940/

===Glossary===
----
===Reference list===

2018 Group Project 1

2018-10-14T04:34:10Z

Z5113627: /* Abnormalities/abnormal development */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===
[[User:Z5014972|Z5014972]] ([[User talk:Z5014972|talk]]) 12:47, 14 August 2018 (AEST)z5014972
good review article https://link.springer.com/article/10.1007%2Fs12022-009-9070-6
----

The neural crest of an embryo differentiates and migrates to form various components of the body. One of these tissues is the medulla of the adrenal gland which is involved in the production of adrenalin and noradrenalin. This project will comprehensively outline the history of neural crest research, the embryonic developmental time course, tissue and organ structure, molecular mechanisms, abnormalities, animal models and current research.

===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.
[[File:NC Location.jpg|left|450px|thumb|The neural crest]]

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniably lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Embryonic origins===
----
[[File:Trunk_NCC_migration.jpg|left|450px|thumb|Trunk NCC migration]]
The adrenal gland is made up of the adrenal cortex and adrenal medulla, which both have different embryonic origins. The adrenal medulla arises from the neural crest tissue, found near the level of the coeliac plexus & sympathetic ganglion at somites 18-24 {{#pmid:16124976|PMID16124976}}. Specifically, this neural crest tissue comes from the trunk neural crest cells (see above figure to determine the approximate location in an embryo) <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
The trunk neural crest coordinates the development of the endocrine system, secretory cells, the peripheral nervous system and, to some degree, skeletal development, as well as innervation of the intestine {{#pmid: 28287247|PMID 28287247}}. The trunk neural cells arise caudally, undergo an epithelial to mesenchymal transition and follow three migratory pathways {{#pmid:20399766|PMID20399766}}.
[[File:Differentiation_of_NCC.jpg|left|580px|thumb|Differentiation of chromaffin cells]]
- A dorsolateral pathway (between ectoderm and somites), these become melanocytes, travel up to the point of the dermis and become a major part of the hair follicles and skin <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
- A ventrolateral pathway (through the somites)
- A ventromedial pathway (between neural tube and posterior schlerotome){{#pmid:20399766|PMID20399766}}.

Migration of neural crest cells from the sympathetic ganglion is what leads to the development of the adrenal medulla. In week 8 of development, immature cells called neuroblasts migrate through to the inner portion of the medulla, where they become the adrenal medulla {{#pmid:19683477|PMID19683477}}. Chromaffin cells are neuroendocrine cells and are found in the sympathetic ganglia and make up the majority of the adrenal medulla{{#pmid:19683477|PMID19683477}}. They synthesise and release a range of hormones in the body and arise from the temporary neural crest. The term chromaffin was inspired by the staining capacity of these cells when they came into contact with chrome salts. They make, store, export and use catecholamines, responsible for making noradrenaline and originate at the caudal region of somites 18-24 of the neural crest, also known as the adrenomedullary region {{#pmid:19683477|PMID19683477}}.

For cells to leave the neural crest and begin their migration, certain conditions need to be met, that is, the cells need to be loosely connected, their tight junctions becoming relaxed, initiated by "Slug protein" and a loss of N-Cadherin which also leads to the loosening of these junctions. The surrounding matrix as well as chemotactic and stem cell factors of the neural tube are then what dictates how the neural crest cells move, some proteins stopping their migration to that area and others encouraging the movement <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. After splitting apart, the first neural crest cells move ventrally and pass into the spaces between the somites and then, through the anterior portions of each segment until they arrive at the para-aortic sites, where they become the cells of the sympathetic ganglia and the adrenal medulla {{#pmid:19683477|PMID19683477}}. BMP-4 (bone morphogenetic protein 4) then acts on these neural crest cells, preventing them from becoming cells that have a neural function and causing them to become chromaffin cells at the adrenal medulla. Glucocorticoids then play a role in maintenance of chromaffin cells in postnatal life, this was only found recently, as previously it was thought that glucocorticoids were responsible entirely for the differentiation of neural crest cells into chromaffin, or adrenomedullary cells {{#pmid:23220335|PMID23220335}}.

===Developmental/adult function===
----
====Normal Structure and Function of the Adrenal Medulla====

The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The medulla contains secretory cells called chromaffin cells, due to the agents they produce when oxidised, such as chromate. These cells secrete epinephrine and norepinephrine in response to various substances such as acetylcholine.

There are three types of cells in the adult adrenal medulla:

* Epinephrine cells
* Norepinephrine cells
* Small granule-containing cells (SGCs)

These cells also produce various other peptides such as substance P and neurotensin. The adrenal medulla also contains presynaptic sympathetic ganglion cells. {{#pmid:1694230|PMID1694230}}

These cells have unique neuroendocrine characteristics as a result of their neural-crest origin. They receive preganglionic innervation by thoracic splanchnic nerves, and could almost be considered a specialised sympathetic ganglion. With postganglgionic bodies, cells of the medulla are densely clustered around their vasculature for the secretion of hormones into the bloodstream to moderate the concentration of epinephrine and norepinephrine.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus. {{#pmid:11215683|PMID11215683}} [[File:Dd.jpg|400px|thumb|right|Adult Adrenal Glands in situ]]

====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses. {{#pmid:19396395|PMID19396395}}

----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

The Adrenal Medulla's neural crest tissue begins at the process of neurulation.

The importance of Somitogenesis and Neural Crest come to a head when neural crest cells must migrate anteriorly from the

Members of the SOX (SRY-Box) gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands.

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well.

[[File:Catecholamine_Synthesis.jpg|500px|thumb|right|Cascade of Catecholamine Synthesis]]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291442/
https://www.ncbi.nlm.nih.gov/pubmed/19396395

===Abnormalities/abnormal development===
----

Abnormalities of the Adrenal Medulla are much less common than its mesoderm-derived shell of the Adrenal Gland. Three of the most notorious abnormalities of the Adrenal Medulla include:

* Pheochromocytomas
* Ganglioneuromas
* Neuroblastomas

Pheochromocytomas-

Ganglioneuromas-

Neuroblastomas-

Apart from these abnormalities, there are other pathologies that may be connected to the adrenal medulla. One such example is a pathology of the Organ of Zuckerkandl. Also known as the para-aortic body, the Organ of Zuckerkandl is a primarily-gestational organ comprised of chromaffin cells.

===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

====Chromaffin cells (in rat models)====
There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells. The neural crest cells give rise to chromaffin cells of the adrenal medulla.

Previous research has reported that nueral crest cells differentiate into chromaffin cells around 19 days of gestation before forming the adrenal medulla{{#pmid:28684471|PMID2868441}}. Past research had also suggested that neural crest derived adrenal gland cells migrate using the sympathetic ganglia to the adrenal gland or preaortic ganglion, following different pathways, to reach their specific destination. However the results have shown that the pathways used to reach its destinations overlapped. This would suggest that there is a possibility of the cells using the same pathway to move from the beginning production to the destination that is the adrenal medulla (for chromaffin cells) and the preaortic ganglion (other cells involved in the sympathetic system).

One particular study done by M.Yamato in 2004, along with his fellow scientists attempted to study the migration of neural crest cells in Wistar rats. In order to observe the formation adrenal medulla from the neural crest cells during the embryonic period, Yamato used anti - tyrosine hydroxylase (TH) antiserum injected into the rat embryos between 13-17 days of gestation. The anti - TH antiserum stain allows the scientists to visualize the neural crest cells under a light microscope. Later three dimensional images were created. From the images observed between 13 to 15 days of gestation, the TH - positive cells can be seen to move from the dorsal to the adrenal primordium{{#pmid:15240937|PMID15240937}}. After 16 days it was observed that a capsule had formed in some parts and TH - positive cells had penetrated the adrenal gland{{#pmid:15240937|PMID15240937}}. At seventeen days, TH - positive cells can be seen collecting at the medial part of the adrenal gland. The reconstructed images also shows that at the later stages during the 16-17 days of gestation, the accumulation of TH - positive cells grow and in combination with cell division leads to the formation of the adrenal medulla.

(Pubmed: 15240937)

Unedited

The finding that the line of TH - positive cells toward the adrenal gland almost disappeared at 17 days of gestation in the reconstructed image suggests that the migration of neural crest - derived cells to the adrenal gland is complete by the 17 days of gestation, after which the formation of the adrenal medulla is completed by cell division in the adrenal gland
Since TH is used in this study as an indicator of chromaffin cells (adrenal medullary cells) is an enzyme involved in the early stage of the synthetic pathway of adrenaline and noradrenaline, the TH - positive cells observed in this study may include not only chromaffin cells but also sympathetic ganglion cells and SIF cells.
It was previously thught that when neural crest - derived cells migrated via the sympatheti chain gangli into the adrenal gland or preaortic ganglion, they took different pathways to the respective destination at the time of passage through the ganglia of the sympathetic trunk.
However, the reconstructed images in this study showed that the pathway of neural crest - deriveed cells from the ganglia of the sympathetic trunk to the adrenal medulla overlapped with the pathway to the preaortic ganglion. We speculate that neural crest cells use the same pathway to migrate to the ganglia of the sympathetic trunk, to the adrenal gland, and to the preaortic ganglion, this onclusion is good agreement of the suggestion by Ahoren.
Ahonen suggested that some neural crest cells continue migration from the chain ganglia to the lateral sides of aorta, where they form the perirenal ganglia and adrenal medulla, and finally to the ventral side of the aorta to form the preaortic sympathetic tissue. However, that report only showed the several transverse sections of the fetal trunk for the a demonstration of the migration route of neural crest cells. In this study, using three dimensional reconstructed images, we aimed to observe how TH-labeled chromaffin cells penetrate into the adrenal anlage to form the adrenal medulla and whether the migration route of TH - positive cells from the adrenal connects the preaortic sympathetic ganglia
(M.Yamato, R. Yanai, K. Arishima, 2004)

Prenatal adrenal gland development has been described in numerous published reports covering a wide variety of species, including the ox (Katznelson, 1966; Wrobel and Suss, 1999), sheep (Davies, 1950; Wintour et al., 1975; Upadhyay and Zamboni, 1982; Naaman‐Reperant and Durand, 1997; Grino, 2004), swine (Sokolov et al., 2006) and mouse (Waring, 1935; Ikeda et al., 1994; Sass, 1996; Nyska and Maronpot, 1999; Bland et al., 2003; Val et al., 2007). Adrenal gland development also has been extensively described for humans as well (Kolliker, 1879; Minot, 1892; Zuckerkandl, 1912; Wieman, 1920; Ikeda et al., 1981; Langlois et al., 2002; Hanley and Arit, 2006).

https://www.sciencedirect.com/science/article/pii/S0925477302004550
http://dev.biologists.org/content/develop/126/13/2935.full.pdf

===Current research (labs)===
----
As explained above the adrenal medulla plays an important part in the autonomic system of an adult human. The chromaffin cells, in particular, are important neural crest derived cell that is closely related to the adrenal medulla. Previous findings have focused specifically on the mechanisms controlling the NCC migration and how these cells go on to form the different derivatives in their particular destinations in the embryo. For example, as previously explained studies have shown that chromaffin cells have been observed to move to the adrenal gland to form the medulla of the adrenal gland.
The findings presented until now have focused on the mechanisms controlling migration along the dorsolateral path. In comparison, our understanding of the mechanisms controlling NCC migration along the ventral path are complicated by the fact that this population comprises multiple precursors that form different derivatives in distinct regions of the embryo. For example, ventrally migrating NCCs either stop within the sclerotome in close association with the neural tube to form neurons and glia of the sensory nervous system (i.e. the dorsal root ganglia [DRG]), while other NCCs continue to migrate further ventrally to form the autonomic nervous system (i.e. sympathetic ganglia and chromaffin cells of the adrenal gland)

<ref>https://onlinelibrary.wiley.com/doi/pdf/10.1111/dgd.12189</ref>

https://onlinelibrary.wiley.com/doi/pdf/10.1111/dgd.12189

Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/

===Glossary===
----
===Reference list===

2018 Group Project 1

2018-10-13T17:05:37Z

Z5113627: /* Genes and Transcription Factors Involved with the Adrenal Medulla's Development */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===
[[User:Z5014972|Z5014972]] ([[User talk:Z5014972|talk]]) 12:47, 14 August 2018 (AEST)z5014972
good review article https://link.springer.com/article/10.1007%2Fs12022-009-9070-6
----

The neural crest of an embryo differentiates and migrates to form various components of the body. One of these tissues is the medulla of the adrenal gland which is involved in the production of adrenalin and noradrenalin. This project will comprehensively outline the history of neural crest research, the embryonic developmental time course, tissue and organ structure, molecular mechanisms, abnormalities, animal models and current research.

===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.
[[File:NC Location.jpg|left|450px|thumb|The neural crest]]

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniably lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Embryonic origins===
----
[[File:Trunk_NCC_migration.jpg|left|450px|thumb|Trunk NCC migration]]
The adrenal gland is made up of the adrenal cortex and adrenal medulla, which both have different embryonic origins. The adrenal medulla arises from the neural crest tissue, found near the level of the coeliac plexus & sympathetic ganglion at somites 18-24 {{#pmid:16124976|PMID16124976}}. Specifically, this neural crest tissue comes from the trunk neural crest cells (see above figure to determine the approximate location in an embryo) <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
The trunk neural crest coordinates the development of the endocrine system, secretory cells, the peripheral nervous system and, to some degree, skeletal development, as well as innervation of the intestine {{#pmid: 28287247|PMID 28287247}}. The trunk neural cells arise caudally, undergo an epithelial to mesenchymal transition and follow three migratory pathways {{#pmid:20399766|PMID20399766}}.
[[File:Differentiation_of_NCC.jpg|left|580px|thumb|Differentiation of chromaffin cells]]
- A dorsolateral pathway (between ectoderm and somites), these become melanocytes, travel up to the point of the dermis and become a major part of the hair follicles and skin <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
- A ventrolateral pathway (through the somites)
- A ventromedial pathway (between neural tube and posterior schlerotome){{#pmid:20399766|PMID20399766}}.

Migration of neural crest cells from the sympathetic ganglion is what leads to the development of the adrenal medulla. In week 8 of development, immature cells called neuroblasts migrate through to the inner portion of the medulla, where they become the adrenal medulla {{#pmid:19683477|PMID19683477}}. Chromaffin cells are neuroendocrine cells and are found in the sympathetic ganglia and make up the majority of the adrenal medulla{{#pmid:19683477|PMID19683477}}. They synthesise and release a range of hormones in the body and arise from the temporary neural crest. The term chromaffin was inspired by the staining capacity of these cells when they came into contact with chrome salts. They make, store, export and use catecholamines, responsible for making noradrenaline and originate at the caudal region of somites 18-24 of the neural crest, also known as the adrenomedullary region {{#pmid:19683477|PMID19683477}}.

For cells to leave the neural crest and begin their migration, certain conditions need to be met, that is, the cells need to be loosely connected, their tight junctions becoming relaxed, initiated by "Slug protein" and a loss of N-Cadherin which also leads to the loosening of these junctions. The surrounding matrix as well as chemotactic and stem cell factors of the neural tube are then what dictates how the neural crest cells move, some proteins stopping their migration to that area and others encouraging the movement <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. After splitting apart, the first neural crest cells move ventrally and pass into the spaces between the somites and then, through the anterior portions of each segment until they arrive at the para-aortic sites, where they become the cells of the sympathetic ganglia and the adrenal medulla {{#pmid:19683477|PMID19683477}}. BMP-4 (bone morphogenetic protein 4) then acts on these neural crest cells, preventing them from becoming cells that have a neural function and causing them to become chromaffin cells at the adrenal medulla. Glucocorticoids then play a role in maintenance of chromaffin cells in postnatal life, this was only found recently, as previously it was thought that glucocorticoids were responsible entirely for the differentiation of neural crest cells into chromaffin, or adrenomedullary cells {{#pmid:23220335|PMID23220335}}.

===Developmental/adult function===
----
====Normal Structure and Function of the Adrenal Medulla====

The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The medulla contains secretory cells called chromaffin cells, due to the agents they produce when oxidised, such as chromate. These cells secrete epinephrine and norepinephrine in response to various substances such as acetylcholine.

There are three types of cells in the adult adrenal medulla:

* Epinephrine cells
* Norepinephrine cells
* Small granule-containing cells (SGCs)

These cells also produce various other peptides such as substance P and neurotensin. The adrenal medulla also contains presynaptic sympathetic ganglion cells. {{#pmid:1694230|PMID1694230}}

These cells have unique neuroendocrine characteristics as a result of their neural-crest origin. They receive preganglionic innervation by thoracic splanchnic nerves, and could almost be considered a specialised sympathetic ganglion. With postganglgionic bodies, cells of the medulla are densely clustered around their vasculature for the secretion of hormones into the bloodstream to moderate the concentration of epinephrine and norepinephrine.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus. {{#pmid:11215683|PMID11215683}} [[File:Dd.jpg|400px|thumb|right|Adult Adrenal Glands in situ]]

====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses. {{#pmid:19396395|PMID19396395}}

----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

The Adrenal Medulla's neural crest tissue begins at the process of neurulation.

The importance of Somitogenesis and Neural Crest come to a head when neural crest cells must migrate anteriorly from the

Members of the SOX (SRY-Box) gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands.

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well.

[[File:Catecholamine_Synthesis.jpg|500px|thumb|right|Cascade of Catecholamine Synthesis]]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291442/
https://www.ncbi.nlm.nih.gov/pubmed/19396395

===Abnormalities/abnormal development===
----

Abnormalities of the Adrenal Medulla are much less common than its mesoderm-derived shell of the Adrenal Gland. Three of the most notorious abnormalities of the Adrenal Medulla include:

* Pheochromocytomas
* Ganglioneuromas
* Neuroblastomas

===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

====Chromaffin cells (in rat models)====
There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells. The neural crest cells give rise to chromaffin cells of the adrenal medulla.

One particular study done by M.Yamato in 2004, along with his fellow scientists attempted to study the migration of neural crest cells in Wistar rats. In order to observe the formation adrenal medulla from the neural crest cells during the embryonic period, Yamato used anti - tyrosine hydroxylase (TH) antiserum injected into the rat embryos between 13-17 days of gestation. The anti - TH antiserum stain allows the scientists to visualize the neural crest cells under a light microscope. Later three dimensional images were created. From the images observed between 13 to 15 days of gestation, the TH - positive cells can be seen to move from the dorsal to the adrenal primordium{{#pmid:15240937|PMID15240937}}. After 16 days it was observed that a capsule had formed in some parts and TH - positive cells had penetrated the adrenal gland{{#pmid:15240937|PMID15240937}}. At seventeen days, TH - positive cells can be seen collecting at the medial part of the adrenal gland.

{{#pmid:15240937|PMID15240937}}.
(Pubmed: 15240937)

Previous research has reported that nueral crest cells differentiate into chromaffin cells around 19 days of gestation before forming the adrenal medulla{{#pmid:28684471|PMID2868441}}. Past research had also suggested that neural crest derived adrenal gland cells migrate using the sympathetic ganglia to the adrenal gland or preaortic ganglion, following different pathways, to reach their specific destination. However the results have shown that the pathways used to reach its destinations overlapped. This would suggest that there is a possibility of the cells using the same pathway to move from the beginning production to the destination that is the adrenal medulla (for chromaffin cells) and the preaortic ganglion (other cells involved in the sympathetic system).

Unedited
Since TH is used in this study as an indicator of chromaffin cells (adrenal medullary cells) is an enzyme involved in the early stage of the synthetic pathway of adrenaline and noradrenaline, the TH - positive cells observed in this study may include not only chromaffin cells but also sympathetic ganglion cells and SIF cells.
It was previously thught that when neural crest - derived cells migrated via the sympatheti chain gangli into the adrenal gland or preaortic ganglion, they took different pathways to the respective destination at the time of passage through the ganglia of the sympathetic trunk.
However, the reconstructed images in this study showed that the pathway of neural crest - deriveed cells from the ganglia of the sympathetic trunk to the adrenal medulla overlapped with the pathway to the preaortic ganglion. We speculate that neural crest cells use the same pathway to migrate to the ganglia of the sympathetic trunk, to the adrenal gland, and to the preaortic ganglion, this onclusion is good agreement of the suggestion by Ahoren.
Ahonen suggested that some neural crest cells continue migration from the chain ganglia to the lateral sides of aorta, where they form the perirenal ganglia and adrenal medulla, and finally to the ventral side of the aorta to form the preaortic sympathetic tissue. However, that report only showed the several transverse sections of the fetal trunk for the a demonstration of the migration route of neural crest cells. In this study, using three dimensional reconstructed images, we aimed to observe how TH-labeled chromaffin cells penetrate into the adrenal anlage to form the adrenal medulla and whether the migration route of TH - positive cells from the adrenal connects the preaortic sympathetic ganglia
(M.Yamato, R. Yanai, K. Arishima, 2004)

Prenatal adrenal gland development has been described in numerous published reports covering a wide variety of species, including the ox (Katznelson, 1966; Wrobel and Suss, 1999), sheep (Davies, 1950; Wintour et al., 1975; Upadhyay and Zamboni, 1982; Naaman‐Reperant and Durand, 1997; Grino, 2004), swine (Sokolov et al., 2006) and mouse (Waring, 1935; Ikeda et al., 1994; Sass, 1996; Nyska and Maronpot, 1999; Bland et al., 2003; Val et al., 2007). Adrenal gland development also has been extensively described for humans as well (Kolliker, 1879; Minot, 1892; Zuckerkandl, 1912; Wieman, 1920; Ikeda et al., 1981; Langlois et al., 2002; Hanley and Arit, 2006).

https://www.sciencedirect.com/science/article/pii/S0925477302004550
http://dev.biologists.org/content/develop/126/13/2935.full.pdf

===Current research (labs)===
----
As explained above the adrenal medulla plays an important part in the autonomic system of an adult human. The chromaffin cells, in particular, are important neural crest derived cell that is closely related to the adrenal medulla.
The findings presented until now have focused on the mechanisms controlling migration along the dorsolateral path. In comparison, our understanding of the mechanisms controlling NCC migration along the ventral path are complicated by the fact that this population comprises multiple precursors that form different derivatives in distinct regions of the embryo. For example, ventrally migrating NCCs either stop within the sclerotome in close association with the neural tube to form neurons and glia of the sensory nervous system (i.e. the dorsal root ganglia [DRG]), while other NCCs continue to migrate further ventrally to form the autonomic nervous system (i.e. sympathetic ganglia and chromaffin cells of the adrenal gland)

https://onlinelibrary.wiley.com/doi/pdf/10.1111/dgd.12189

Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/

===Glossary===
----
===Reference list===

2018 Group Project 1

2018-10-13T16:49:27Z

Z5113627: /* Normal Structure and Function of the Adrenal Medulla */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===
[[User:Z5014972|Z5014972]] ([[User talk:Z5014972|talk]]) 12:47, 14 August 2018 (AEST)z5014972
good review article https://link.springer.com/article/10.1007%2Fs12022-009-9070-6
----

The neural crest of an embryo differentiates and migrates to form various components of the body. One of these tissues is the medulla of the adrenal gland which is involved in the production of adrenalin and noradrenalin. This project will comprehensively outline the history of neural crest research, the embryonic developmental time course, tissue and organ structure, molecular mechanisms, abnormalities, animal models and current research.

===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.
[[File:NC Location.jpg|left|450px|thumb|The neural crest]]

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniably lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Embryonic origins===
----
[[File:Trunk_NCC_migration.jpg|left|450px|thumb|Trunk NCC migration]]
The adrenal gland is made up of the adrenal cortex and adrenal medulla, which both have different embryonic origins. The adrenal medulla arises from the neural crest tissue, found near the level of the coeliac plexus & sympathetic ganglion at somites 18-24 {{#pmid:16124976|PMID16124976}}. Specifically, this neural crest tissue comes from the trunk neural crest cells (see above figure to determine the approximate location in an embryo) <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
The trunk neural crest coordinates the development of the endocrine system, secretory cells, the peripheral nervous system and, to some degree, skeletal development, as well as innervation of the intestine {{#pmid: 28287247|PMID 28287247}}. The trunk neural cells arise caudally, undergo an epithelial to mesenchymal transition and follow three migratory pathways {{#pmid:20399766|PMID20399766}}.
[[File:Differentiation_of_NCC.jpg|left|580px|thumb|Differentiation of chromaffin cells]]
- A dorsolateral pathway (between ectoderm and somites), these become melanocytes, travel up to the point of the dermis and become a major part of the hair follicles and skin <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
- A ventrolateral pathway (through the somites)
- A ventromedial pathway (between neural tube and posterior schlerotome){{#pmid:20399766|PMID20399766}}.

Migration of neural crest cells from the sympathetic ganglion is what leads to the development of the adrenal medulla. In week 8 of development, immature cells called neuroblasts migrate through to the inner portion of the medulla, where they become the adrenal medulla {{#pmid:19683477|PMID19683477}}. Chromaffin cells are neuroendocrine cells and are found in the sympathetic ganglia and make up the majority of the adrenal medulla{{#pmid:19683477|PMID19683477}}. They synthesise and release a range of hormones in the body and arise from the temporary neural crest. The term chromaffin was inspired by the staining capacity of these cells when they came into contact with chrome salts. They make, store, export and use catecholamines, responsible for making noradrenaline and originate at the caudal region of somites 18-24 of the neural crest, also known as the adrenomedullary region {{#pmid:19683477|PMID19683477}}.

For cells to leave the neural crest and begin their migration, certain conditions need to be met, that is, the cells need to be loosely connected, their tight junctions becoming relaxed, initiated by "Slug protein" and a loss of N-Cadherin which also leads to the loosening of these junctions. The surrounding matrix as well as chemotactic and stem cell factors of the neural tube are then what dictates how the neural crest cells move, some proteins stopping their migration to that area and others encouraging the movement <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. After splitting apart, the first neural crest cells move ventrally and pass into the spaces between the somites and then, through the anterior portions of each segment until they arrive at the para-aortic sites, where they become the cells of the sympathetic ganglia and the adrenal medulla {{#pmid:19683477|PMID19683477}}. BMP-4 (bone morphogenetic protein 4) then acts on these neural crest cells, preventing them from becoming cells that have a neural function and causing them to become chromaffin cells at the adrenal medulla. Glucocorticoids then play a role in maintenance of chromaffin cells in postnatal life, this was only found recently, as previously it was thought that glucocorticoids were responsible entirely for the differentiation of neural crest cells into chromaffin, or adrenomedullary cells {{#pmid:23220335|PMID23220335}}.

===Developmental/adult function===
----
====Normal Structure and Function of the Adrenal Medulla====

The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The medulla contains secretory cells called chromaffin cells, due to the agents they produce when oxidised, such as chromate. These cells secrete epinephrine and norepinephrine in response to various substances such as acetylcholine.

There are three types of cells in the adult adrenal medulla:

* Epinephrine cells
* Norepinephrine cells
* Small granule-containing cells (SGCs)

These cells also produce various other peptides such as substance P and neurotensin. The adrenal medulla also contains presynaptic sympathetic ganglion cells. {{#pmid:1694230|PMID1694230}}

These cells have unique neuroendocrine characteristics as a result of their neural-crest origin. They receive preganglionic innervation by thoracic splanchnic nerves, and could almost be considered a specialised sympathetic ganglion. With postganglgionic bodies, cells of the medulla are densely clustered around their vasculature for the secretion of hormones into the bloodstream to moderate the concentration of epinephrine and norepinephrine.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus. {{#pmid:11215683|PMID11215683}} [[File:Dd.jpg|400px|thumb|right|Adult Adrenal Glands in situ]]

====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses. {{#pmid:19396395|PMID19396395}}

----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

Members of the SOX (SRY-Box) gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands.

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well.

[[File:Catecholamine_Synthesis.jpg|500px|thumb|right|Cascade of Catecholamine Synthesis]]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291442/
https://www.ncbi.nlm.nih.gov/pubmed/19396395

===Abnormalities/abnormal development===
----

Abnormalities of the Adrenal Medulla are much less common than its mesoderm-derived shell of the Adrenal Gland. Three of the most notorious abnormalities of the Adrenal Medulla include:

* Pheochromocytomas
* Ganglioneuromas
* Neuroblastomas

===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

====Chromaffin cells (in rat models)====
There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells. The neural crest cells give rise to chromaffin cells of the adrenal medulla.

One particular study done by M.Yamato in 2004, along with his fellow scientists attempted to study the migration of neural crest cells in Wistar rats. In order to observe the formation adrenal medulla from the neural crest cells during the embryonic period, Yamato used anti - tyrosine hydroxylase (TH) antiserum injected into the rat embryos between 13-17 days of gestation. The anti - TH antiserum stain allows the scientists to visualize the neural crest cells under a light microscope. Later three dimensional images were created. From the images observed between 13 to 15 days of gestation, the TH - positive cells can be seen to move from the dorsal to the adrenal primordium{{#pmid:15240937|PMID15240937}}. After 16 days it was observed that a capsule had formed in some parts and TH - positive cells had penetrated the adrenal gland{{#pmid:15240937|PMID15240937}}. At seventeen days, TH - positive cells can be seen collecting at the medial part of the adrenal gland.

{{#pmid:15240937|PMID15240937}}.
(Pubmed: 15240937)

Previous research has reported that nueral crest cells differentiate into chromaffin cells around 19 days of gestation before forming the adrenal medulla{{#pmid:28684471|PMID2868441}}. Past research had also suggested that neural crest derived adrenal gland cells migrate using the sympathetic ganglia to the adrenal gland or preaortic ganglion, following different pathways, to reach their specific destination. However the results have shown that the pathways used to reach its destinations overlapped. This would suggest that there is a possibility of the cells using the same pathway to move from the beginning production to the destination that is the adrenal medulla (for chromaffin cells) and the preaortic ganglion (other cells involved in the sympathetic system).

Unedited
Since TH is used in this study as an indicator of chromaffin cells (adrenal medullary cells) is an enzyme involved in the early stage of the synthetic pathway of adrenaline and noradrenaline, the TH - positive cells observed in this study may include not only chromaffin cells but also sympathetic ganglion cells and SIF cells.
It was previously thught that when neural crest - derived cells migrated via the sympatheti chain gangli into the adrenal gland or preaortic ganglion, they took different pathways to the respective destination at the time of passage through the ganglia of the sympathetic trunk.
However, the reconstructed images in this study showed that the pathway of neural crest - deriveed cells from the ganglia of the sympathetic trunk to the adrenal medulla overlapped with the pathway to the preaortic ganglion. We speculate that neural crest cells use the same pathway to migrate to the ganglia of the sympathetic trunk, to the adrenal gland, and to the preaortic ganglion, this onclusion is good agreement of the suggestion by Ahoren.
Ahonen suggested that some neural crest cells continue migration from the chain ganglia to the lateral sides of aorta, where they form the perirenal ganglia and adrenal medulla, and finally to the ventral side of the aorta to form the preaortic sympathetic tissue. However, that report only showed the several transverse sections of the fetal trunk for the a demonstration of the migration route of neural crest cells. In this study, using three dimensional reconstructed images, we aimed to observe how TH-labeled chromaffin cells penetrate into the adrenal anlage to form the adrenal medulla and whether the migration route of TH - positive cells from the adrenal connects the preaortic sympathetic ganglia
(M.Yamato, R. Yanai, K. Arishima, 2004)

Prenatal adrenal gland development has been described in numerous published reports covering a wide variety of species, including the ox (Katznelson, 1966; Wrobel and Suss, 1999), sheep (Davies, 1950; Wintour et al., 1975; Upadhyay and Zamboni, 1982; Naaman‐Reperant and Durand, 1997; Grino, 2004), swine (Sokolov et al., 2006) and mouse (Waring, 1935; Ikeda et al., 1994; Sass, 1996; Nyska and Maronpot, 1999; Bland et al., 2003; Val et al., 2007). Adrenal gland development also has been extensively described for humans as well (Kolliker, 1879; Minot, 1892; Zuckerkandl, 1912; Wieman, 1920; Ikeda et al., 1981; Langlois et al., 2002; Hanley and Arit, 2006).

https://www.sciencedirect.com/science/article/pii/S0925477302004550
http://dev.biologists.org/content/develop/126/13/2935.full.pdf

===Current research (labs)===
----
As explained above the adrenal medulla plays an important part in the autonomic system of an adult human. The chromaffin cells, in particular, are important neural crest derived cell that is closely related to the adrenal medulla.
The findings presented until now have focused on the mechanisms controlling migration along the dorsolateral path. In comparison, our understanding of the mechanisms controlling NCC migration along the ventral path are complicated by the fact that this population comprises multiple precursors that form different derivatives in distinct regions of the embryo. For example, ventrally migrating NCCs either stop within the sclerotome in close association with the neural tube to form neurons and glia of the sensory nervous system (i.e. the dorsal root ganglia [DRG]), while other NCCs continue to migrate further ventrally to form the autonomic nervous system (i.e. sympathetic ganglia and chromaffin cells of the adrenal gland)

https://onlinelibrary.wiley.com/doi/pdf/10.1111/dgd.12189

Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/

===Glossary===
----
===Reference list===

2018 Group Project 1

2018-10-13T16:05:58Z

Z5113627: /* Normal Structure and Function of the Adrenal Medulla */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===
[[User:Z5014972|Z5014972]] ([[User talk:Z5014972|talk]]) 12:47, 14 August 2018 (AEST)z5014972
good review article https://link.springer.com/article/10.1007%2Fs12022-009-9070-6
----

The neural crest of an embryo differentiates and migrates to form various components of the body. One of these tissues is the medulla of the adrenal gland which is involved in the production of adrenalin and noradrenalin. This project will comprehensively outline the history of neural crest research, the embryonic developmental time course, tissue and organ structure, molecular mechanisms, abnormalities, animal models and current research.

===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.
[[File:NC Location.jpg|left|450px|thumb|The neural crest]]

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniably lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Embryonic origins===
----
[[File:Trunk_NCC_migration.jpg|left|450px|thumb|Trunk NCC migration]]
The adrenal gland is made up of the adrenal cortex and adrenal medulla, which both have different embryonic origins. The adrenal medulla arises from the neural crest tissue, found near the level of the coeliac plexus & sympathetic ganglion at somites 18-24 {{#pmid:16124976|PMID16124976}}. Specifically, this neural crest tissue comes from the trunk neural crest cells (see above figure to determine the approximate location in an embryo) <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
The trunk neural crest coordinates the development of the endocrine system, secretory cells, the peripheral nervous system and, to some degree, skeletal development, as well as innervation of the intestine {{#pmid: 28287247|PMID 28287247}}. The trunk neural cells arise caudally, undergo an epithelial to mesenchymal transition and follow three migratory pathways {{#pmid:20399766|PMID20399766}}.
[[File:Differentiation_of_NCC.jpg|left|580px|thumb|Differentiation of chromaffin cells]]
- A dorsolateral pathway (between ectoderm and somites), these become melanocytes, travel up to the point of the dermis and become a major part of the hair follicles and skin <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
- A ventrolateral pathway (through the somites)
- A ventromedial pathway (between neural tube and posterior schlerotome){{#pmid:20399766|PMID20399766}}.

Migration of neural crest cells from the sympathetic ganglion is what leads to the development of the adrenal medulla. In week 8 of development, immature cells called neuroblasts migrate through to the inner portion of the medulla, where they become the adrenal medulla {{#pmid:19683477|PMID19683477}}. Chromaffin cells are neuroendocrine cells and are found in the sympathetic ganglia and make up the majority of the adrenal medulla{{#pmid:19683477|PMID19683477}}. They synthesise and release a range of hormones in the body and arise from the temporary neural crest. The term chromaffin was inspired by the staining capacity of these cells when they came into contact with chrome salts. They make, store, export and use catecholamines, responsible for making noradrenaline and originate at the caudal region of somites 18-24 of the neural crest, also known as the adrenomedullary region {{#pmid:19683477|PMID19683477}}.

For cells to leave the neural crest and begin their migration, certain conditions need to be met, that is, the cells need to be loosely connected, their tight junctions becoming relaxed, initiated by "Slug protein" and a loss of N-Cadherin which also leads to the loosening of these junctions. The surrounding matrix as well as chemotactic and stem cell factors of the neural tube are then what dictates how the neural crest cells move, some proteins stopping their migration to that area and others encouraging the movement <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. After splitting apart, the first neural crest cells move ventrally and pass into the spaces between the somites and then, through the anterior portions of each segment until they arrive at the para-aortic sites, where they become the cells of the sympathetic ganglia and the adrenal medulla {{#pmid:19683477|PMID19683477}}. BMP-4 (bone morphogenetic protein 4) then acts on these neural crest cells, preventing them from becoming cells that have a neural function and causing them to become chromaffin cells at the adrenal medulla. Glucocorticoids then play a role in maintenance of chromaffin cells in postnatal life, this was only found recently, as previously it was thought that glucocorticoids were responsible entirely for the differentiation of neural crest cells into chromaffin, or adrenomedullary cells {{#pmid:23220335|PMID23220335}}.

===Developmental/adult function===
----
====Normal Structure and Function of the Adrenal Medulla====

The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The medulla contains secretory cells called chromaffin cells, due to the agents they produce when oxidised, such as chromate. These cells secrete epinephrine and norepinephrine in response to various substances such as acetylcholine.

There are three types of cells in the adult adrenal medulla:

* Epinephrine cells
* Norepinephrine cells
* Small granule-containing cells (SGCs)

These cells also produce various other peptides such as substance P and neurotensin. The adrenal medulla also contains presynaptic sympathetic ganglion cells. {{#pmid:1694230|PMID1694230}}

These cells have unique neuroendocrine characteristics as a result of their neural-crest origin. They receive preganglionic innervation by thoracic splanchnic nerves, and could almost be considered a specialised sympathetic ganglion. With postganglgionic bodies, cells of the medulla are densely clustered around their vasculature for the secretion of hormones into the bloodstream to moderate the concentration of epinephrine and norepinephrine.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus. {{#pmid:11215683|PMID11215683}} [[File:Dd.jpg|400px|thumb|right|Adult Adrenal Glands in situ]]

====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses. {{#pmid:19396395|PMID19396395}}

----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

Members of the SOX (SRY-Box) gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands.

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well.

[[File:Catecholamine_Synthesis.jpg|500px|thumb|right|Cascade of Catecholamine Synthesis]]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291442/
https://www.ncbi.nlm.nih.gov/pubmed/19396395

===Abnormalities/abnormal development===
----

Abnormalities of the Adrenal Medulla are much less common than its mesoderm-derived shell of the Adrenal Gland. Three of the most notorious abnormalities of the Adrenal Medulla include:

* Pheochromocytomas
* Ganglioneuromas
* Neuroblastomas

===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

====Chromaffin cells (in rat models)====
There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells. The neural crest cells give rise to chromaffin cells of the adrenal medulla.

One particular study done by M.Yamato in 2004, along with his fellow scientists attempted to study the migration of neural crest cells in Wistar rats. In order to observe the formation adrenal medulla from the neural crest cells during the embryonic period, Yamato used anti - tyrosine hydroxylase (TH) antiserum injected into the rat embryos between 13-17 days of gestation. The anti - TH antiserum stain allows the scientists to visualize the neural crest cells under a light microscope. Later three dimensional images were created. From the images observed between 13 to 15 days of gestation, the TH - positive cells can be seen to move from the dorsal to the adrenal primordium{{#pmid:15240937|PMID15240937}}. After 16 days it was observed that a capsule had formed in some parts and TH - positive cells had penetrated the adrenal gland{{#pmid:15240937|PMID15240937}}. At seventeen days, TH - positive cells can be seen collecting at the medial part of the adrenal gland.

{{#pmid:15240937|PMID15240937}}.
(Pubmed: 15240937)

Previous research has reported that nueral crest cells differentiate into chromaffin cells around 19 days of gestation before forming the adrenal medulla{{#pmid:28684471|PMID2868441}}. Past research had also suggested that neural crest derived adrenal gland cells migrate using the sympathetic ganglia to the adrenal gland or preaortic ganglion, following different pathways, to reach their specific destination. However the results have shown that the pathways used to reach its destinations overlapped. This would suggest that there is a possibility of the cells using the same pathway to move from the beginning production to the destination that is the adrenal medulla (for chromaffin cells) and the preaortic ganglion (other cells involved in the sympathetic system).

Unedited
Since TH is used in this study as an indicator of chromaffin cells (adrenal medullary cells) is an enzyme involved in the early stage of the synthetic pathway of adrenaline and noradrenaline, the TH - positive cells observed in this study may include not only chromaffin cells but also sympathetic ganglion cells and SIF cells.
It was previously thught that when neural crest - derived cells migrated via the sympatheti chain gangli into the adrenal gland or preaortic ganglion, they took different pathways to the respective destination at the time of passage through the ganglia of the sympathetic trunk.
However, the reconstructed images in this study showed that the pathway of neural crest - deriveed cells from the ganglia of the sympathetic trunk to the adrenal medulla overlapped with the pathway to the preaortic ganglion. We speculate that neural crest cells use the same pathway to migrate to the ganglia of the sympathetic trunk, to the adrenal gland, and to the preaortic ganglion, this onclusion is good agreement of the suggestion by Ahoren.
Ahonen suggested that some neural crest cells continue migration from the chain ganglia to the lateral sides of aorta, where they form the perirenal ganglia and adrenal medulla, and finally to the ventral side of the aorta to form the preaortic sympathetic tissue. However, that report only showed the several transverse sections of the fetal trunk for the a demonstration of the migration route of neural crest cells. In this study, using three dimensional reconstructed images, we aimed to observe how TH-labeled chromaffin cells penetrate into the adrenal anlage to form the adrenal medulla and whether the migration route of TH - positive cells from the adrenal connects the preaortic sympathetic ganglia
(M.Yamato, R. Yanai, K. Arishima, 2004)

Prenatal adrenal gland development has been described in numerous published reports covering a wide variety of species, including the ox (Katznelson, 1966; Wrobel and Suss, 1999), sheep (Davies, 1950; Wintour et al., 1975; Upadhyay and Zamboni, 1982; Naaman‐Reperant and Durand, 1997; Grino, 2004), swine (Sokolov et al., 2006) and mouse (Waring, 1935; Ikeda et al., 1994; Sass, 1996; Nyska and Maronpot, 1999; Bland et al., 2003; Val et al., 2007). Adrenal gland development also has been extensively described for humans as well (Kolliker, 1879; Minot, 1892; Zuckerkandl, 1912; Wieman, 1920; Ikeda et al., 1981; Langlois et al., 2002; Hanley and Arit, 2006).

https://www.sciencedirect.com/science/article/pii/S0925477302004550
http://dev.biologists.org/content/develop/126/13/2935.full.pdf

===Current research (labs)===
----
As explained above the adrenal medulla plays an important part in the autonomic system of an adult human. The chromaffin cells, in particular, are important neural crest derived cell that is closely related to the adrenal medulla.
The findings presented until now have focused on the mechanisms controlling migration along the dorsolateral path. In comparison, our understanding of the mechanisms controlling NCC migration along the ventral path are complicated by the fact that this population comprises multiple precursors that form different derivatives in distinct regions of the embryo. For example, ventrally migrating NCCs either stop within the sclerotome in close association with the neural tube to form neurons and glia of the sensory nervous system (i.e. the dorsal root ganglia [DRG]), while other NCCs continue to migrate further ventrally to form the autonomic nervous system (i.e. sympathetic ganglia and chromaffin cells of the adrenal gland)

https://onlinelibrary.wiley.com/doi/pdf/10.1111/dgd.12189

Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/

===Glossary===
----
===Reference list===

2018 Group Project 1

2018-10-13T16:05:18Z

Z5113627: /* Abnormalities/abnormal development */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===
[[User:Z5014972|Z5014972]] ([[User talk:Z5014972|talk]]) 12:47, 14 August 2018 (AEST)z5014972
good review article https://link.springer.com/article/10.1007%2Fs12022-009-9070-6
----

The neural crest of an embryo differentiates and migrates to form various components of the body. One of these tissues is the medulla of the adrenal gland which is involved in the production of adrenalin and noradrenalin. This project will comprehensively outline the history of neural crest research, the embryonic developmental time course, tissue and organ structure, molecular mechanisms, abnormalities, animal models and current research.

===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.
[[File:NC Location.jpg|left|450px|thumb|The neural crest]]

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniably lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Embryonic origins===
----
[[File:Trunk_NCC_migration.jpg|left|450px|thumb|Trunk NCC migration]]
The adrenal gland is made up of the adrenal cortex and adrenal medulla, which both have different embryonic origins. The adrenal medulla arises from the neural crest tissue, found near the level of the coeliac plexus & sympathetic ganglion at somites 18-24 {{#pmid:16124976|PMID16124976}}. Specifically, this neural crest tissue comes from the trunk neural crest cells (see above figure to determine the approximate location in an embryo) <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
The trunk neural crest coordinates the development of the endocrine system, secretory cells, the peripheral nervous system and, to some degree, skeletal development, as well as innervation of the intestine {{#pmid: 28287247|PMID 28287247}}. The trunk neural cells arise caudally, undergo an epithelial to mesenchymal transition and follow three migratory pathways {{#pmid:20399766|PMID20399766}}.
[[File:Differentiation_of_NCC.jpg|left|580px|thumb|Differentiation of chromaffin cells]]
- A dorsolateral pathway (between ectoderm and somites), these become melanocytes, travel up to the point of the dermis and become a major part of the hair follicles and skin <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
- A ventrolateral pathway (through the somites)
- A ventromedial pathway (between neural tube and posterior schlerotome){{#pmid:20399766|PMID20399766}}.

Migration of neural crest cells from the sympathetic ganglion is what leads to the development of the adrenal medulla. In week 8 of development, immature cells called neuroblasts migrate through to the inner portion of the medulla, where they become the adrenal medulla {{#pmid:19683477|PMID19683477}}. Chromaffin cells are neuroendocrine cells and are found in the sympathetic ganglia and make up the majority of the adrenal medulla{{#pmid:19683477|PMID19683477}}. They synthesise and release a range of hormones in the body and arise from the temporary neural crest. The term chromaffin was inspired by the staining capacity of these cells when they came into contact with chrome salts. They make, store, export and use catecholamines, responsible for making noradrenaline and originate at the caudal region of somites 18-24 of the neural crest, also known as the adrenomedullary region {{#pmid:19683477|PMID19683477}}.

For cells to leave the neural crest and begin their migration, certain conditions need to be met, that is, the cells need to be loosely connected, their tight junctions becoming relaxed, initiated by "Slug protein" and a loss of N-Cadherin which also leads to the loosening of these junctions. The surrounding matrix as well as chemotactic and stem cell factors of the neural tube are then what dictates how the neural crest cells move, some proteins stopping their migration to that area and others encouraging the movement <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. After splitting apart, the first neural crest cells move ventrally and pass into the spaces between the somites and then, through the anterior portions of each segment until they arrive at the para-aortic sites, where they become the cells of the sympathetic ganglia and the adrenal medulla {{#pmid:19683477|PMID19683477}}. BMP-4 (bone morphogenetic protein 4) then acts on these neural crest cells, preventing them from becoming cells that have a neural function and causing them to become chromaffin cells at the adrenal medulla. Glucocorticoids then play a role in maintenance of chromaffin cells in postnatal life, this was only found recently, as previously it was thought that glucocorticoids were responsible entirely for the differentiation of neural crest cells into chromaffin, or adrenomedullary cells {{#pmid:23220335|PMID23220335}}.

===Developmental/adult function===
----
====Normal Structure and Function of the Adrenal Medulla====

The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The medulla contains secretory cells called chromaffin cells, due to the agents they produce when oxidised, such as chromate. These cells secrete epinephrine and norepinephrine in response to various substances such as acetylcholine.

There are three types of cells in the adult adrenal medulla:

1) Epinephrine cells

2) Norepinephrine cells

3) Small granule-containing cells (SGCs)

These cells also produce various other peptides such as substance P and neurotensin. The adrenal medulla also contains presynaptic sympathetic ganglion cells. {{#pmid:1694230|PMID1694230}}

These cells have unique neuroendocrine characteristics as a result of their neural-crest origin. They receive preganglionic innervation by thoracic splanchnic nerves, and could almost be considered a specialised sympathetic ganglion. With postganglgionic bodies, cells of the medulla are densely clustered around their vasculature for the secretion of hormones into the bloodstream to moderate the concentration of epinephrine and norepinephrine.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus. {{#pmid:11215683|PMID11215683}} [[File:Dd.jpg|400px|thumb|right|Adult Adrenal Glands in situ]]

====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses. {{#pmid:19396395|PMID19396395}}

----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

Members of the SOX (SRY-Box) gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands.

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well.

[[File:Catecholamine_Synthesis.jpg|500px|thumb|right|Cascade of Catecholamine Synthesis]]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291442/
https://www.ncbi.nlm.nih.gov/pubmed/19396395

===Abnormalities/abnormal development===
----

Abnormalities of the Adrenal Medulla are much less common than its mesoderm-derived shell of the Adrenal Gland. Three of the most notorious abnormalities of the Adrenal Medulla include:

* Pheochromocytomas
* Ganglioneuromas
* Neuroblastomas

===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

====Chromaffin cells (in rat models)====
There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells. The neural crest cells give rise to chromaffin cells of the adrenal medulla.

One particular study done by M.Yamato in 2004, along with his fellow scientists attempted to study the migration of neural crest cells in Wistar rats. In order to observe the formation adrenal medulla from the neural crest cells during the embryonic period, Yamato used anti - tyrosine hydroxylase (TH) antiserum injected into the rat embryos between 13-17 days of gestation. The anti - TH antiserum stain allows the scientists to visualize the neural crest cells under a light microscope. Later three dimensional images were created. From the images observed between 13 to 15 days of gestation, the TH - positive cells can be seen to move from the dorsal to the adrenal primordium{{#pmid:15240937|PMID15240937}}. After 16 days it was observed that a capsule had formed in some parts and TH - positive cells had penetrated the adrenal gland{{#pmid:15240937|PMID15240937}}. At seventeen days, TH - positive cells can be seen collecting at the medial part of the adrenal gland.

{{#pmid:15240937|PMID15240937}}.
(Pubmed: 15240937)

Previous research has reported that nueral crest cells differentiate into chromaffin cells around 19 days of gestation before forming the adrenal medulla{{#pmid:28684471|PMID2868441}}. Past research had also suggested that neural crest derived adrenal gland cells migrate using the sympathetic ganglia to the adrenal gland or preaortic ganglion, following different pathways, to reach their specific destination. However the results have shown that the pathways used to reach its destinations overlapped. This would suggest that there is a possibility of the cells using the same pathway to move from the beginning production to the destination that is the adrenal medulla (for chromaffin cells) and the preaortic ganglion (other cells involved in the sympathetic system).

Unedited
Since TH is used in this study as an indicator of chromaffin cells (adrenal medullary cells) is an enzyme involved in the early stage of the synthetic pathway of adrenaline and noradrenaline, the TH - positive cells observed in this study may include not only chromaffin cells but also sympathetic ganglion cells and SIF cells.
It was previously thught that when neural crest - derived cells migrated via the sympatheti chain gangli into the adrenal gland or preaortic ganglion, they took different pathways to the respective destination at the time of passage through the ganglia of the sympathetic trunk.
However, the reconstructed images in this study showed that the pathway of neural crest - deriveed cells from the ganglia of the sympathetic trunk to the adrenal medulla overlapped with the pathway to the preaortic ganglion. We speculate that neural crest cells use the same pathway to migrate to the ganglia of the sympathetic trunk, to the adrenal gland, and to the preaortic ganglion, this onclusion is good agreement of the suggestion by Ahoren.
Ahonen suggested that some neural crest cells continue migration from the chain ganglia to the lateral sides of aorta, where they form the perirenal ganglia and adrenal medulla, and finally to the ventral side of the aorta to form the preaortic sympathetic tissue. However, that report only showed the several transverse sections of the fetal trunk for the a demonstration of the migration route of neural crest cells. In this study, using three dimensional reconstructed images, we aimed to observe how TH-labeled chromaffin cells penetrate into the adrenal anlage to form the adrenal medulla and whether the migration route of TH - positive cells from the adrenal connects the preaortic sympathetic ganglia
(M.Yamato, R. Yanai, K. Arishima, 2004)

Prenatal adrenal gland development has been described in numerous published reports covering a wide variety of species, including the ox (Katznelson, 1966; Wrobel and Suss, 1999), sheep (Davies, 1950; Wintour et al., 1975; Upadhyay and Zamboni, 1982; Naaman‐Reperant and Durand, 1997; Grino, 2004), swine (Sokolov et al., 2006) and mouse (Waring, 1935; Ikeda et al., 1994; Sass, 1996; Nyska and Maronpot, 1999; Bland et al., 2003; Val et al., 2007). Adrenal gland development also has been extensively described for humans as well (Kolliker, 1879; Minot, 1892; Zuckerkandl, 1912; Wieman, 1920; Ikeda et al., 1981; Langlois et al., 2002; Hanley and Arit, 2006).

https://www.sciencedirect.com/science/article/pii/S0925477302004550
http://dev.biologists.org/content/develop/126/13/2935.full.pdf

===Current research (labs)===
----
As explained above the adrenal medulla plays an important part in the autonomic system of an adult human. The chromaffin cells, in particular, are important neural crest derived cell that is closely related to the adrenal medulla.
The findings presented until now have focused on the mechanisms controlling migration along the dorsolateral path. In comparison, our understanding of the mechanisms controlling NCC migration along the ventral path are complicated by the fact that this population comprises multiple precursors that form different derivatives in distinct regions of the embryo. For example, ventrally migrating NCCs either stop within the sclerotome in close association with the neural tube to form neurons and glia of the sensory nervous system (i.e. the dorsal root ganglia [DRG]), while other NCCs continue to migrate further ventrally to form the autonomic nervous system (i.e. sympathetic ganglia and chromaffin cells of the adrenal gland)

https://onlinelibrary.wiley.com/doi/pdf/10.1111/dgd.12189

Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/

===Glossary===
----
===Reference list===

2018 Group Project 1

2018-10-13T04:15:29Z

Z5113627: /* Tissue and Organ structure */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===
[[User:Z5014972|Z5014972]] ([[User talk:Z5014972|talk]]) 12:47, 14 August 2018 (AEST)z5014972
good review article https://link.springer.com/article/10.1007%2Fs12022-009-9070-6
----

The neural crest of an embryo differentiates and migrates to form various components of the body. One of these tissues is the medulla of the adrenal gland which is involved in the production of adrenalin and noradrenalin. This project will comprehensively outline the history of neural crest research, the embryonic developmental time course, tissue and organ structure, molecular mechanisms, abnormalities, animal models and current research.

===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.
[[File:NC Location.jpg|left|450px|thumb|The neural crest]]

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniably lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Embryonic origins===
----
[[File:Trunk_NCC_migration.jpg|left|450px|thumb|Trunk NCC migration]]
The adrenal gland is made up of the adrenal cortex and adrenal medulla, which both have different embryonic origins. The adrenal medulla arises from the neural crest tissue, found near the level of the coeliac plexus & sympathetic ganglion at somites 18-24 {{#pmid:16124976|PMID16124976}}. Specifically, this neural crest tissue comes from the trunk neural crest cells (see above figure to determine the approximate location in an embryo) <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
The trunk neural crest coordinates the development of the endocrine system, secretory cells, the peripheral nervous system and, to some degree, skeletal development, as well as innervation of the intestine {{#pmid: 28287247|PMID 28287247}}. The trunk neural cells arise caudally, undergo an epithelial to mesenchymal transition and follow three migratory pathways {{#pmid:20399766|PMID20399766}}.
[[File:Differentiation_of_NCC.jpg|left|580px|thumb|Differentiation of chromaffin cells]]
- A dorsolateral pathway (between ectoderm and somites), these become melanocytes, travel up to the point of the dermis and become a major part of the hair follicles and skin <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
- A ventrolateral pathway (through the somites)
- A ventromedial pathway (between neural tube and posterior schlerotome){{#pmid:20399766|PMID20399766}}.

Migration of neural crest cells from the sympathetic ganglion is what leads to the development of the adrenal medulla. In week 8 of development, immature cells called neuroblasts migrate through to the inner portion of the medulla, where they become the adrenal medulla {{#pmid:19683477|PMID19683477}}. Chromaffin cells are neuroendocrine cells and are found in the sympathetic ganglia and make up the majority of the adrenal medulla{{#pmid:19683477|PMID19683477}}. They synthesise and release a range of hormones in the body and arise from the temporary neural crest. The term chromaffin was inspired by the staining capacity of these cells when they came into contact with chrome salts. They make, store, export and use catecholamines, responsible for making noradrenaline and originate at the caudal region of somites 18-24 of the neural crest, also known as the adrenomedullary region {{#pmid:19683477|PMID19683477}}.

For cells to leave the neural crest and begin their migration, certain conditions need to be met, that is, the cells need to be loosely connected, their tight junctions becoming relaxed, initiated by "Slug protein" and a loss of N-Cadherin which also leads to the loosening of these junctions. The surrounding matrix as well as chemotactic and stem cell factors of the neural tube are then what dictates how the neural crest cells move, some proteins stopping their migration to that area and others encouraging the movement <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. After splitting apart, the first neural crest cells move ventrally and pass into the spaces between the somites and then, through the anterior portions of each segment until they arrive at the para-aortic sites, where they become the cells of the sympathetic ganglia and the adrenal medulla {{#pmid:19683477|PMID19683477}}. BMP-4 (bone morphogenetic protein 4) then acts on these neural crest cells, preventing them from becoming cells that have a neural function and causing them to become chromaffin cells at the adrenal medulla. Glucocorticoids then play a role in maintenance of chromaffin cells in postnatal life, this was only found recently, as previously it was thought that glucocorticoids were responsible entirely for the differentiation of neural crest cells into chromaffin, or adrenomedullary cells {{#pmid:23220335|PMID23220335}}.

===Developmental/adult function===
----
====Normal Structure and Function of the Adrenal Medulla====

The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The medulla contains secretory cells called chromaffin cells, due to the agents they produce when oxidised, such as chromate. These cells secrete epinephrine and norepinephrine in response to various substances such as acetylcholine.

There are three types of cells in the adult adrenal medulla:

1) Epinephrine cells

2) Norepinephrine cells

3) Small granule-containing cells (SGCs)

These cells also produce various other peptides such as substance P and neurotensin. The adrenal medulla also contains presynaptic sympathetic ganglion cells. {{#pmid:1694230|PMID1694230}}

These cells have unique neuroendocrine characteristics as a result of their neural-crest origin. They receive preganglionic innervation by thoracic splanchnic nerves, and could almost be considered a specialised sympathetic ganglion. With postganglgionic bodies, cells of the medulla are densely clustered around their vasculature for the secretion of hormones into the bloodstream to moderate the concentration of epinephrine and norepinephrine.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus. {{#pmid:11215683|PMID11215683}} [[File:Dd.jpg|400px|thumb|right|Adult Adrenal Glands in situ]]

====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses. {{#pmid:19396395|PMID19396395}}

----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

Members of the SOX (SRY-Box) gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands.

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well.

[[File:Catecholamine_Synthesis.jpg|500px|thumb|right|Cascade of Catecholamine Synthesis]]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291442/
https://www.ncbi.nlm.nih.gov/pubmed/19396395

===Abnormalities/abnormal development===
----

Abnormalities of the Adrenal Medulla are much less common than its mesoderm-derived shell of the Adrenal Gland. Pheochromocytoma is the most notorious abnormality of the Adrenal Medulla.

===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

====Chromaffin cells (in rat models)====
There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells. The neural crest cells give rise to chromaffin cells of the adrenal medulla.

To study the formation process of the adrenal medulla in the embryonic period, we visualized chromaffin cells of rat embryos at 13 to 17 days of gestation using anti-tyrosine hydroxylase (TH) antiserum, and created three-dimensional images from serial tissue sections. Between 13 and 15 days of gestation, TH-positive cells (chromaffin cells) migrated from a group of TH-positive cells present dorsal to the adrenal primordium via the medial cranial end of the adrenal primordium into the adrenal primordium. At or after 16 days of gestation, the adrenal capsule was formed except on the ventral aspect of the cranial end of the adrenal gland, from which TH-positive cells penetrated into the adrenal gland.(Pubmed: 15240937)

Past research has reported that nueral crest cells
migrate into sympathetic ganglia and the adrenal cortex and almost completely convert t chromaffin cells by 19 days of gestation, forming the adrenal medulla. Since TH is used in this study as an indicator of chromaffin cells (adrenal medullary cells) is an enzyme involved in the early stage of the synthetic pathway of adrenaline and noradrenaline, the TH - positive cells observed in this study may include not only chromaffin cells but also sympathetic ganglion cells and SIF cells.
It was previously thught that when neural crest - derived cells migrated via the sympatheti chain gangli into the adrenal gland or preaortic ganglion, they took different pathways to the respective destination at the time of passage through the ganglia of the sympathetic trunk.
However, the reconstructed images in this study showed that the pathway of neural crest - deriveed cells from the ganglia of the sympathetic trunk to the adrenal medulla overlapped with the pathway to the preaortic ganglion. We speculate that neural crest cells use the same pathway to migrate to the ganglia of the sympathetic trunk, to the adrenal gland, and to the preaortic ganglion, this onclusion is good agreement of the suggestion by Ahoren.
Ahonen suggested that some neural crest cells continue migration from the chain ganglia to the lateral sides of aorta, where they form the perirenal ganglia and adrenal medulla, and finally to the ventral side of the aorta to form the preaortic sympathetic tissue. However, that report only showed the several transverse sections of the fetal trunk for the a demonstration of the migration route of neural crest cells. In this study, using three dimensional reconstructed images, we aimed to observe how TH-labeled chromaffin cells penetrate into the adrenal anlage to form the adrenal medulla and whether the migration route of TH - positive cells from the adrenal connects the preaortic sympathetic ganglia
(M.Yamato, R. Yanai, K. Arishima, 2004)

Prenatal adrenal gland development has been described in numerous published reports covering a wide variety of species, including the ox (Katznelson, 1966; Wrobel and Suss, 1999), sheep (Davies, 1950; Wintour et al., 1975; Upadhyay and Zamboni, 1982; Naaman‐Reperant and Durand, 1997; Grino, 2004), swine (Sokolov et al., 2006) and mouse (Waring, 1935; Ikeda et al., 1994; Sass, 1996; Nyska and Maronpot, 1999; Bland et al., 2003; Val et al., 2007). Adrenal gland development also has been extensively described for humans as well (Kolliker, 1879; Minot, 1892; Zuckerkandl, 1912; Wieman, 1920; Ikeda et al., 1981; Langlois et al., 2002; Hanley and Arit, 2006).

https://www.sciencedirect.com/science/article/pii/S0925477302004550
http://dev.biologists.org/content/develop/126/13/2935.full.pdf

===Current research (labs)===
----
The findings presented until now have focused on the mechanisms controlling migration along the dorsolateral path. In comparison, our understanding of the mechanisms controlling NCC migration along the ventral path are complicated by the fact that this population comprises multiple precursors that form different derivatives in distinct regions of the embryo. For example, ventrally migrating NCCs either stop within the sclerotome in close association with the neural tube to form neurons and glia of the sensory nervous system (i.e. the dorsal root ganglia [DRG]), while other NCCs continue to migrate further ventrally to form the autonomic nervous system (i.e. sympathetic ganglia and chromaffin cells of the adrenal gland)

Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/

===Glossary===
----
===Reference list===

2018 Group Project 1

2018-10-12T13:45:00Z

Z5113627: /* Tissue and Organ structure */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===
[[User:Z5014972|Z5014972]] ([[User talk:Z5014972|talk]]) 12:47, 14 August 2018 (AEST)z5014972
good review article https://link.springer.com/article/10.1007%2Fs12022-009-9070-6
----

The neural crest of an embryo differentiates and migrates to form various components of the body. One of these tissues is the medulla of the adrenal gland which is involved in the production of adrenalin and noradrenalin. This project will comprehensively outline the history of neural crest research, the embryonic developmental time course, tissue and organ structure, molecular mechanisms, abnormalities, animal models and current research.

===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.
[[File:NC Location.jpg|left|450px|thumb|The neural crest]]

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniably lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Embryonic origins===
----
[[File:Trunk_NCC_migration.jpg|left|450px|thumb|Trunk NCC migration]]
The adrenal gland is made up of the adrenal cortex and adrenal medulla, which both have different embryonic origins. The adrenal medulla arises from the neural crest tissue, found near the level of the coeliac plexus & sympathetic ganglion at somites 18-24 {{#pmid:16124976|PMID16124976}}. Specifically, this neural crest tissue comes from the trunk neural crest cells (see above figure to determine the approximate location in an embryo) <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
The trunk neural crest coordinates the development of the endocrine system, secretory cells, the peripheral nervous system and, to some degree, skeletal development, as well as innervation of the intestine {{#pmid: 28287247|PMID 28287247}}. The trunk neural cells arise caudally, undergo an epithelial to mesenchymal transition and follow three migratory pathways {{#pmid:20399766|PMID20399766}}.
[[File:Differentiation_of_NCC.jpg|left|580px|thumb|Differentiation of chromaffin cells]]
- A dorsolateral pathway (between ectoderm and somites), these become melanocytes, travel up to the point of the dermis and become a major part of the hair follicles and skin <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
- A ventrolateral pathway (through the somites)
- A ventromedial pathway (between neural tube and posterior schlerotome){{#pmid:20399766|PMID20399766}}.

Migration of neural crest cells from the sympathetic ganglion is what leads to the development of the adrenal medulla. In week 8 of development, immature cells called neuroblasts migrate through to the inner portion of the medulla, where they become the adrenal medulla {{#pmid:19683477|PMID19683477}}. Chromaffin cells are neuroendocrine cells and are found in the sympathetic ganglia and make up the majority of the adrenal medulla{{#pmid:19683477|PMID19683477}}. They synthesise and release a range of hormones in the body and arise from the temporary neural crest. The term chromaffin was inspired by the staining capacity of these cells when they came into contact with chrome salts. They make, store, export and use catecholamines, responsible for making noradrenaline and originate at the caudal region of somites 18-24 of the neural crest, also known as the adrenomedullary region {{#pmid:19683477|PMID19683477}}.

For cells to leave the neural crest and begin their migration, certain conditions need to be met, that is, the cells need to be loosely connected, their tight junctions becoming relaxed, initiated by "Slug protein" and a loss of N-Cadherin which also leads to the loosening of these junctions. The surrounding matrix as well as chemotactic and stem cell factors of the neural tube are then what dictates how the neural crest cells move, some proteins stopping their migration to that area and others encouraging the movement <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. After splitting apart, the first neural crest cells move ventrally and pass into the spaces between the somites and then, through the anterior portions of each segment until they arrive at the para-aortic sites, where they become the cells of the sympathetic ganglia and the adrenal medulla {{#pmid:19683477|PMID19683477}}. BMP-4 (bone morphogenetic protein 4) then acts on these neural crest cells, preventing them from becoming cells that have a neural function and causing them to become chromaffin cells at the adrenal medulla. Glucocorticoids then play a role in maintenance of chromaffin cells in postnatal life, this was only found recently, as previously it was thought that glucocorticoids were responsible entirely for the differentiation of neural crest cells into chromaffin, or adrenomedullary cells {{#pmid:23220335|PMID23220335}}.

===Developmental/adult function===
----
===Tissue and Organ structure===

====Normal Structure and Function of the Adrenal Medulla====

The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The medulla contains secretory cells called chromaffin cells, due to the agents they produce when oxidised, such as chromate. These cells secrete epinephrine and norepinephrine in response to various substances such as acetylcholine.

There are three types of cells in the adult adrenal medulla:
1) Epinephrine cells

2) Norepinephrine cells

3) Small granule-containing cells (SGCs)

These cells also produce various other peptides such as substance P and neurotensin. The adrenal medulla also contains presynaptic sympathetic ganglion cells. {{#pmid:1694230|PMID1694230}}

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus. {{#pmid:11215683|PMID11215683}} [[File:Dd.jpg|400px|thumb|right|Adult Adrenal Glands in situ]]

====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses. {{#pmid:19396395|PMID19396395}}

----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

Members of the SOX (SRY-Box) gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands.

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well.

[[File:Catecholamine_Synthesis.jpg|500px|thumb|right|Cascade of Catecholamine Synthesis]]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291442/
https://www.ncbi.nlm.nih.gov/pubmed/19396395

===Abnormalities/abnormal development===
----

Abnormalities of the Adrenal Medulla are much less common than its mesoderm-derived shell of the Adrenal Gland. Pheochromocytoma is the most notorious abnormality of the Adrenal Medulla.

===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

====Chromaffin cells (in rat models)====
There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells. The neural crest cells give rise to chromaffin cells of the adrenal medulla.

To study the formation process of the adrenal medulla in the embryonic period, we visualized chromaffin cells of rat embryos at 13 to 17 days of gestation using anti-tyrosine hydroxylase (TH) antiserum, and created three-dimensional images from serial tissue sections. Between 13 and 15 days of gestation, TH-positive cells (chromaffin cells) migrated from a group of TH-positive cells present dorsal to the adrenal primordium via the medial cranial end of the adrenal primordium into the adrenal primordium. At or after 16 days of gestation, the adrenal capsule was formed except on the ventral aspect of the cranial end of the adrenal gland, from which TH-positive cells penetrated into the adrenal gland.(Pubmed: 15240937)

Past research has reported that nueral crest cells
migrate into sympathetic ganglia and the adrenal cortex and almost completely convert t chromaffin cells by 19 days of gestation, forming the adrenal medulla. Since TH is used in this study as an indicator of chromaffin cells (adrenal medullary cells) is an enzyme involved in the early stage of the synthetic pathway of adrenaline and noradrenaline, the TH - positive cells observed in this study may include not only chromaffin cells but also sympathetic ganglion cells and SIF cells.
It was previously thught that when neural crest - derived cells migrated via the sympatheti chain gangli into the adrenal gland or preaortic ganglion, they took different pathways to the respective destination at the time of passage through the ganglia of the sympathetic trunk.
However, the reconstructed images in this study showed that the pathway of neural crest - deriveed cells from the ganglia of the sympathetic trunk to the adrenal medulla overlapped with the pathway to the preaortic ganglion. We speculate that neural crest cells use the same pathway to migrate to the ganglia of the sympathetic trunk, to the adrenal gland, and to the preaortic ganglion, this onclusion is good agreement of the suggestion by Ahoren.
Ahonen suggested that some neural crest cells continue migration from the chain ganglia to the lateral sides of aorta, where they form the perirenal ganglia and adrenal medulla, and finally to the ventral side of the aorta to form the preaortic sympathetic tissue. However, that report only showed the several transverse sections of the fetal trunk for the a demonstration of the migration route of neural crest cells. In this study, using three dimensional reconstructed images, we aimed to observe how TH-labeled chromaffin cells penetrate into the adrenal anlage to form the adrenal medulla and whether the migration route of TH - positive cells from the adrenal connects the preaortic sympathetic ganglia
(M.Yamato, R. Yanai, K. Arishima, 2004)

Prenatal adrenal gland development has been described in numerous published reports covering a wide variety of species, including the ox (Katznelson, 1966; Wrobel and Suss, 1999), sheep (Davies, 1950; Wintour et al., 1975; Upadhyay and Zamboni, 1982; Naaman‐Reperant and Durand, 1997; Grino, 2004), swine (Sokolov et al., 2006) and mouse (Waring, 1935; Ikeda et al., 1994; Sass, 1996; Nyska and Maronpot, 1999; Bland et al., 2003; Val et al., 2007). Adrenal gland development also has been extensively described for humans as well (Kolliker, 1879; Minot, 1892; Zuckerkandl, 1912; Wieman, 1920; Ikeda et al., 1981; Langlois et al., 2002; Hanley and Arit, 2006).

https://www.sciencedirect.com/science/article/pii/S0925477302004550
http://dev.biologists.org/content/develop/126/13/2935.full.pdf

===Current research (labs)===
----
The findings presented until now have focused on the mechanisms controlling migration along the dorsolateral path. In comparison, our understanding of the mechanisms controlling NCC migration along the ventral path are complicated by the fact that this population comprises multiple precursors that form different derivatives in distinct regions of the embryo. For example, ventrally migrating NCCs either stop within the sclerotome in close association with the neural tube to form neurons and glia of the sensory nervous system (i.e. the dorsal root ganglia [DRG]), while other NCCs continue to migrate further ventrally to form the autonomic nervous system (i.e. sympathetic ganglia and chromaffin cells of the adrenal gland)

Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/

===Glossary===
----
===Reference list===

2018 Group Project 1

2018-10-12T13:44:13Z

Z5113627: /* Abnormalities/abnormal development */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===
[[User:Z5014972|Z5014972]] ([[User talk:Z5014972|talk]]) 12:47, 14 August 2018 (AEST)z5014972
good review article https://link.springer.com/article/10.1007%2Fs12022-009-9070-6
----

The neural crest of an embryo differentiates and migrates to form various components of the body. One of these tissues is the medulla of the adrenal gland which is involved in the production of adrenalin and noradrenalin. This project will comprehensively outline the history of neural crest research, the embryonic developmental time course, tissue and organ structure, molecular mechanisms, abnormalities, animal models and current research.

===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.
[[File:NC Location.jpg|left|450px|thumb|The neural crest]]

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniably lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Embryonic origins===
----
[[File:Trunk_NCC_migration.jpg|left|450px|thumb|Trunk NCC migration]]
The adrenal gland is made up of the adrenal cortex and adrenal medulla, which both have different embryonic origins. The adrenal medulla arises from the neural crest tissue, found near the level of the coeliac plexus & sympathetic ganglion at somites 18-24 {{#pmid:16124976|PMID16124976}}. Specifically, this neural crest tissue comes from the trunk neural crest cells (see above figure to determine the approximate location in an embryo) <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
The trunk neural crest coordinates the development of the endocrine system, secretory cells, the peripheral nervous system and, to some degree, skeletal development, as well as innervation of the intestine {{#pmid: 28287247|PMID 28287247}}. The trunk neural cells arise caudally, undergo an epithelial to mesenchymal transition and follow three migratory pathways {{#pmid:20399766|PMID20399766}}.
[[File:Differentiation_of_NCC.jpg|left|580px|thumb|Differentiation of chromaffin cells]]
- A dorsolateral pathway (between ectoderm and somites), these become melanocytes, travel up to the point of the dermis and become a major part of the hair follicles and skin <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
- A ventrolateral pathway (through the somites)
- A ventromedial pathway (between neural tube and posterior schlerotome){{#pmid:20399766|PMID20399766}}.

Migration of neural crest cells from the sympathetic ganglion is what leads to the development of the adrenal medulla. In week 8 of development, immature cells called neuroblasts migrate through to the inner portion of the medulla, where they become the adrenal medulla {{#pmid:19683477|PMID19683477}}. Chromaffin cells are neuroendocrine cells and are found in the sympathetic ganglia and make up the majority of the adrenal medulla{{#pmid:19683477|PMID19683477}}. They synthesise and release a range of hormones in the body and arise from the temporary neural crest. The term chromaffin was inspired by the staining capacity of these cells when they came into contact with chrome salts. They make, store, export and use catecholamines, responsible for making noradrenaline and originate at the caudal region of somites 18-24 of the neural crest, also known as the adrenomedullary region {{#pmid:19683477|PMID19683477}}.

For cells to leave the neural crest and begin their migration, certain conditions need to be met, that is, the cells need to be loosely connected, their tight junctions becoming relaxed, initiated by "Slug protein" and a loss of N-Cadherin which also leads to the loosening of these junctions. The surrounding matrix as well as chemotactic and stem cell factors of the neural tube are then what dictates how the neural crest cells move, some proteins stopping their migration to that area and others encouraging the movement <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. After splitting apart, the first neural crest cells move ventrally and pass into the spaces between the somites and then, through the anterior portions of each segment until they arrive at the para-aortic sites, where they become the cells of the sympathetic ganglia and the adrenal medulla {{#pmid:19683477|PMID19683477}}. BMP-4 (bone morphogenetic protein 4) then acts on these neural crest cells, preventing them from becoming cells that have a neural function and causing them to become chromaffin cells at the adrenal medulla. Glucocorticoids then play a role in maintenance of chromaffin cells in postnatal life, this was only found recently, as previously it was thought that glucocorticoids were responsible entirely for the differentiation of neural crest cells into chromaffin, or adrenomedullary cells {{#pmid:23220335|PMID23220335}}.

===Developmental/adult function===
----
===Tissue and Organ structure===

====Normal Structure and Function of the Adrenal Medulla====

The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The medulla contains secretory cells called chromaffin cells, due to the agents they produce when oxidised, such as chromate. These cells secrete epinephrine and norepinephrine in response to various substances such as acetylcholine.

There are three types of cells in the adult adrenal medulla:
1) Epinephrine cells

2) Norepinephrine cells

3) Small granule-containing cells (SGCs)

These cells also produce various other peptides such as substance P and neurotensin. The adrenal medulla also contains presynaptic sympathetic ganglion cells. {{#pmid:1694230|PMID1694230}}

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus. {{#pmid:11215683|PMID11215683}}

====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses. {{#pmid:19396395|PMID19396395}}

[[File:Dd.jpg|400px|thumb|right|Adult Adrenal Glands in situ]]
----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

Members of the SOX (SRY-Box) gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands.

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well.

[[File:Catecholamine_Synthesis.jpg|500px|thumb|right|Cascade of Catecholamine Synthesis]]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291442/
https://www.ncbi.nlm.nih.gov/pubmed/19396395

===Abnormalities/abnormal development===
----

Abnormalities of the Adrenal Medulla are much less common than its mesoderm-derived shell of the Adrenal Gland. Pheochromocytoma is the most notorious abnormality of the Adrenal Medulla.

===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

====Chromaffin cells (in rat models)====
There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells. The neural crest cells give rise to chromaffin cells of the adrenal medulla.

To study the formation process of the adrenal medulla in the embryonic period, we visualized chromaffin cells of rat embryos at 13 to 17 days of gestation using anti-tyrosine hydroxylase (TH) antiserum, and created three-dimensional images from serial tissue sections. Between 13 and 15 days of gestation, TH-positive cells (chromaffin cells) migrated from a group of TH-positive cells present dorsal to the adrenal primordium via the medial cranial end of the adrenal primordium into the adrenal primordium. At or after 16 days of gestation, the adrenal capsule was formed except on the ventral aspect of the cranial end of the adrenal gland, from which TH-positive cells penetrated into the adrenal gland.(Pubmed: 15240937)

Past research has reported that nueral crest cells
migrate into sympathetic ganglia and the adrenal cortex and almost completely convert t chromaffin cells by 19 days of gestation, forming the adrenal medulla. Since TH is used in this study as an indicator of chromaffin cells (adrenal medullary cells) is an enzyme involved in the early stage of the synthetic pathway of adrenaline and noradrenaline, the TH - positive cells observed in this study may include not only chromaffin cells but also sympathetic ganglion cells and SIF cells.
It was previously thught that when neural crest - derived cells migrated via the sympatheti chain gangli into the adrenal gland or preaortic ganglion, they took different pathways to the respective destination at the time of passage through the ganglia of the sympathetic trunk.
However, the reconstructed images in this study showed that the pathway of neural crest - deriveed cells from the ganglia of the sympathetic trunk to the adrenal medulla overlapped with the pathway to the preaortic ganglion. We speculate that neural crest cells use the same pathway to migrate to the ganglia of the sympathetic trunk, to the adrenal gland, and to the preaortic ganglion, this onclusion is good agreement of the suggestion by Ahoren.
Ahonen suggested that some neural crest cells continue migration from the chain ganglia to the lateral sides of aorta, where they form the perirenal ganglia and adrenal medulla, and finally to the ventral side of the aorta to form the preaortic sympathetic tissue. However, that report only showed the several transverse sections of the fetal trunk for the a demonstration of the migration route of neural crest cells. In this study, using three dimensional reconstructed images, we aimed to observe how TH-labeled chromaffin cells penetrate into the adrenal anlage to form the adrenal medulla and whether the migration route of TH - positive cells from the adrenal connects the preaortic sympathetic ganglia
(M.Yamato, R. Yanai, K. Arishima, 2004)

Prenatal adrenal gland development has been described in numerous published reports covering a wide variety of species, including the ox (Katznelson, 1966; Wrobel and Suss, 1999), sheep (Davies, 1950; Wintour et al., 1975; Upadhyay and Zamboni, 1982; Naaman‐Reperant and Durand, 1997; Grino, 2004), swine (Sokolov et al., 2006) and mouse (Waring, 1935; Ikeda et al., 1994; Sass, 1996; Nyska and Maronpot, 1999; Bland et al., 2003; Val et al., 2007). Adrenal gland development also has been extensively described for humans as well (Kolliker, 1879; Minot, 1892; Zuckerkandl, 1912; Wieman, 1920; Ikeda et al., 1981; Langlois et al., 2002; Hanley and Arit, 2006).

https://www.sciencedirect.com/science/article/pii/S0925477302004550
http://dev.biologists.org/content/develop/126/13/2935.full.pdf

===Current research (labs)===
----
The findings presented until now have focused on the mechanisms controlling migration along the dorsolateral path. In comparison, our understanding of the mechanisms controlling NCC migration along the ventral path are complicated by the fact that this population comprises multiple precursors that form different derivatives in distinct regions of the embryo. For example, ventrally migrating NCCs either stop within the sclerotome in close association with the neural tube to form neurons and glia of the sensory nervous system (i.e. the dorsal root ganglia [DRG]), while other NCCs continue to migrate further ventrally to form the autonomic nervous system (i.e. sympathetic ganglia and chromaffin cells of the adrenal gland)

Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/

===Glossary===
----
===Reference list===

2018 Group Project 1

2018-10-12T13:18:35Z

Z5113627: /* Role of the Adrenal Medulla */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===
[[User:Z5014972|Z5014972]] ([[User talk:Z5014972|talk]]) 12:47, 14 August 2018 (AEST)z5014972
good review article https://link.springer.com/article/10.1007%2Fs12022-009-9070-6
----

The neural crest of an embryo differentiates and migrates to form various components of the body. One of these tissues is the medulla of the adrenal gland which is involved in the production of adrenalin and noradrenalin. This project will comprehensively outline the history of neural crest research, the embryonic developmental time course, tissue and organ structure, molecular mechanisms, abnormalities, animal models and current research.

===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.
[[File:NC Location.jpg|left|450px|thumb|The neural crest]]

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniably lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Embryonic origins===
----
[[File:Trunk_NCC_migration.jpg|left|450px|thumb|Trunk NCC migration]]
The adrenal gland is made up of the adrenal cortex and adrenal medulla, which both have different embryonic origins. The adrenal medulla arises from the neural crest tissue, found near the level of the coeliac plexus & sympathetic ganglion at somites 18-24 {{#pmid:16124976|PMID16124976}}. Specifically, this neural crest tissue comes from the trunk neural crest cells (see above figure to determine the approximate location in an embryo) <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
The trunk neural crest coordinates the development of the endocrine system, secretory cells, the peripheral nervous system and, to some degree, skeletal development, as well as innervation of the intestine {{#pmid: 28287247|PMID 28287247}}. The trunk neural cells arise caudally, undergo an epithelial to mesenchymal transition and follow three migratory pathways {{#pmid:20399766|PMID20399766}}.
[[File:Differentiation_of_NCC.jpg|left|580px|thumb|Differentiation of chromaffin cells]]
- A dorsolateral pathway (between ectoderm and somites), these become melanocytes, travel up to the point of the dermis and become a major part of the hair follicles and skin <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
- A ventrolateral pathway (through the somites)
- A ventromedial pathway (between neural tube and posterior schlerotome){{#pmid:20399766|PMID20399766}}.

Migration of neural crest cells from the sympathetic ganglion is what leads to the development of the adrenal medulla. In week 8 of development, immature cells called neuroblasts migrate through to the inner portion of the medulla, where they become the adrenal medulla {{#pmid:19683477|PMID19683477}}. Chromaffin cells are neuroendocrine cells and are found in the sympathetic ganglia and make up the majority of the adrenal medulla{{#pmid:19683477|PMID19683477}}. They synthesise and release a range of hormones in the body and arise from the temporary neural crest. The term chromaffin was inspired by the staining capacity of these cells when they came into contact with chrome salts. They make, store, export and use catecholamines, responsible for making noradrenaline and originate at the caudal region of somites 18-24 of the neural crest, also known as the adrenomedullary region {{#pmid:19683477|PMID19683477}}.

For cells to leave the neural crest and begin their migration, certain conditions need to be met, that is, the cells need to be loosely connected, their tight junctions becoming relaxed, initiated by "Slug protein" and a loss of N-Cadherin which also leads to the loosening of these junctions. The surrounding matrix as well as chemotactic and stem cell factors of the neural tube are then what dictates how the neural crest cells move, some proteins stopping their migration to that area and others encouraging the movement <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. After splitting apart, the first neural crest cells move ventrally and pass into the spaces between the somites and then, through the anterior portions of each segment until they arrive at the para-aortic sites, where they become the cells of the sympathetic ganglia and the adrenal medulla {{#pmid:19683477|PMID19683477}}. BMP-4 (bone morphogenetic protein 4) then acts on these neural crest cells, preventing them from becoming cells that have a neural function and causing them to become chromaffin cells at the adrenal medulla. Glucocorticoids then play a role in maintenance of chromaffin cells in postnatal life, this was only found recently, as previously it was thought that glucocorticoids were responsible entirely for the differentiation of neural crest cells into chromaffin, or adrenomedullary cells {{#pmid:23220335|PMID23220335}}.

===Developmental/adult function===
----
===Tissue and Organ structure===

====Normal Structure and Function of the Adrenal Medulla====

The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The medulla contains secretory cells called chromaffin cells, due to the agents they produce when oxidised, such as chromate. These cells secrete epinephrine and norepinephrine in response to various substances such as acetylcholine.

There are three types of cells in the adult adrenal medulla:
1) Epinephrine cells

2) Norepinephrine cells

3) Small granule-containing cells (SGCs)

These cells also produce various other peptides such as substance P and neurotensin. The adrenal medulla also contains presynaptic sympathetic ganglion cells. {{#pmid:1694230|PMID1694230}}

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus. {{#pmid:11215683|PMID11215683}}

====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses. {{#pmid:19396395|PMID19396395}}

[[File:Dd.jpg|400px|thumb|right|Adult Adrenal Glands in situ]]
----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

Members of the SOX (SRY-Box) gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands.

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well.

[[File:Catecholamine_Synthesis.jpg|500px|thumb|right|Cascade of Catecholamine Synthesis]]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291442/
https://www.ncbi.nlm.nih.gov/pubmed/19396395

===Abnormalities/abnormal development===
----
===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

====Chromaffin cells (in rat models)====
There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells. The neural crest cells give rise to chromaffin cells of the adrenal medulla.

To study the formation process of the adrenal medulla in the embryonic period, we visualized chromaffin cells of rat embryos at 13 to 17 days of gestation using anti-tyrosine hydroxylase (TH) antiserum, and created three-dimensional images from serial tissue sections. Between 13 and 15 days of gestation, TH-positive cells (chromaffin cells) migrated from a group of TH-positive cells present dorsal to the adrenal primordium via the medial cranial end of the adrenal primordium into the adrenal primordium. At or after 16 days of gestation, the adrenal capsule was formed except on the ventral aspect of the cranial end of the adrenal gland, from which TH-positive cells penetrated into the adrenal gland.(Pubmed: 15240937)

Past research has reported that nueral crest cells
migrate into sympathetic ganglia and the adrenal cortex and almost completely convert t chromaffin cells by 19 days of gestation, forming the adrenal medulla. Since TH is used in this study as an indicator of chromaffin cells (adrenal medullary cells) is an enzyme involved in the early stage of the synthetic pathway of adrenaline and noradrenaline, the TH - positive cells observed in this study may include not only chromaffin cells but also sympathetic ganglion cells and SIF cells.
It was previously thught that when neural crest - derived cells migrated via the sympatheti chain gangli into the adrenal gland or preaortic ganglion, they took different pathways to the respective destination at the time of passage through the ganglia of the sympathetic trunk.
However, the reconstructed images in this study showed that the pathway of neural crest - deriveed cells from the ganglia of the sympathetic trunk to the adrenal medulla overlapped with the pathway to the preaortic ganglion. We speculate that neural crest cells use the same pathway to migrate to the ganglia of the sympathetic trunk, to the adrenal gland, and to the preaortic ganglion, this onclusion is good agreement of the suggestion by Ahoren.
Ahonen suggested that some neural crest cells continue migration from the chain ganglia to the lateral sides of aorta, where they form the perirenal ganglia and adrenal medulla, and finally to the ventral side of the aorta to form the preaortic sympathetic tissue. However, that report only showed the several transverse sections of the fetal trunk for the a demonstration of the migration route of neural crest cells. In this study, using three dimensional reconstructed images, we aimed to observe how TH-labeled chromaffin cells penetrate into the adrenal anlage to form the adrenal medulla and whether the migration route of TH - positive cells from the adrenal connects the preaortic sympathetic ganglia
(M.Yamato, R. Yanai, K. Arishima, 2004)

Prenatal adrenal gland development has been described in numerous published reports covering a wide variety of species, including the ox (Katznelson, 1966; Wrobel and Suss, 1999), sheep (Davies, 1950; Wintour et al., 1975; Upadhyay and Zamboni, 1982; Naaman‐Reperant and Durand, 1997; Grino, 2004), swine (Sokolov et al., 2006) and mouse (Waring, 1935; Ikeda et al., 1994; Sass, 1996; Nyska and Maronpot, 1999; Bland et al., 2003; Val et al., 2007). Adrenal gland development also has been extensively described for humans as well (Kolliker, 1879; Minot, 1892; Zuckerkandl, 1912; Wieman, 1920; Ikeda et al., 1981; Langlois et al., 2002; Hanley and Arit, 2006).

https://www.sciencedirect.com/science/article/pii/S0925477302004550
http://dev.biologists.org/content/develop/126/13/2935.full.pdf

===Current research (labs)===
----
The findings presented until now have focused on the mechanisms controlling migration along the dorsolateral path. In comparison, our understanding of the mechanisms controlling NCC migration along the ventral path are complicated by the fact that this population comprises multiple precursors that form different derivatives in distinct regions of the embryo. For example, ventrally migrating NCCs either stop within the sclerotome in close association with the neural tube to form neurons and glia of the sensory nervous system (i.e. the dorsal root ganglia [DRG]), while other NCCs continue to migrate further ventrally to form the autonomic nervous system (i.e. sympathetic ganglia and chromaffin cells of the adrenal gland)

Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/

===Glossary===
----
===Reference list===

2018 Group Project 1

2018-10-12T09:15:13Z

Z5113627: /* Related Anatomy */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===
[[User:Z5014972|Z5014972]] ([[User talk:Z5014972|talk]]) 12:47, 14 August 2018 (AEST)z5014972
good review article https://link.springer.com/article/10.1007%2Fs12022-009-9070-6
----

The neural crest of an embryo differentiates and migrates to form various components of the body. One of these tissues is the medulla of the adrenal gland which is involved in the production of adrenalin and noradrenalin. This project will comprehensively outline the history of neural crest research, the embryonic developmental time course, tissue and organ structure, molecular mechanisms, abnormalities, animal models and current research.

===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.
[[File:NC Location.jpg|left|450px|thumb|The neural crest]]

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniably lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Embryonic origins===
----
[[File:Trunk_NCC_migration.jpg|left|450px|thumb|Trunk NCC migration]]
The adrenal gland is made up of the adrenal cortex and adrenal medulla, which both have different embryonic origins. The adrenal medulla arises from the neural crest tissue, found near the level of the coeliac plexus & sympathetic ganglion at somites 18-24 {{#pmid:16124976|PMID16124976}}. Specifically, this neural crest tissue comes from the trunk neural crest cells (see above figure to determine the approximate location in an embryo) <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
The trunk neural crest coordinates the development of the endocrine system, secretory cells, the peripheral nervous system and, to some degree, skeletal development, as well as innervation of the intestine {{#pmid: 28287247|PMID 28287247}}. The trunk neural cells arise caudally, undergo an epithelial to mesenchymal transition and follow three migratory pathways {{#pmid:20399766|PMID20399766}}.
[[File:Differentiation_of_NCC.jpg|left|580px|thumb|Differentiation of chromaffin cells]]
- A dorsolateral pathway (between ectoderm and somites), these become melanocytes, travel up to the point of the dermis and become a major part of the hair follicles and skin <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
- A ventrolateral pathway (through the somites)
- A ventromedial pathway (between neural tube and posterior schlerotome){{#pmid:20399766|PMID20399766}}.

Migration of neural crest cells from the sympathetic ganglion is what leads to the development of the adrenal medulla. In week 8 of development, immature cells called neuroblasts migrate through to the inner portion of the medulla, where they become the adrenal medulla {{#pmid:19683477|PMID19683477}}. Chromaffin cells are neuroendocrine cells and are found in the sympathetic ganglia and make up the majority of the adrenal medulla{{#pmid:19683477|PMID19683477}}. They synthesise and release a range of hormones in the body and arise from the temporary neural crest. The term chromaffin was inspired by the staining capacity of these cells when they came into contact with chrome salts. They make, store, export and use catecholamines, responsible for making noradrenaline and originate at the caudal region of somites 18-24 of the neural crest, also known as the adrenomedullary region {{#pmid:19683477|PMID19683477}}.

For cells to leave the neural crest and begin their migration, certain conditions need to be met, that is, the cells need to be loosely connected, their tight junctions becoming relaxed, initiated by "Slug protein" and a loss of N-Cadherin which also leads to the loosening of these junctions. The surrounding matrix as well as chemotactic and stem cell factors of the neural tube are then what dictates how the neural crest cells move, some proteins stopping their migration to that area and others encouraging the movement <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. After splitting apart, the first neural crest cells move ventrally and pass into the spaces between the somites and then, through the anterior portions of each segment until they arrive at the para-aortic sites, where they become the cells of the sympathetic ganglia and the adrenal medulla {{#pmid:19683477|PMID19683477}}. BMP-4 (bone morphogenetic protein 4) then acts on these neural crest cells, preventing them from becoming cells that have a neural function and causing them to become chromaffin cells at the adrenal medulla. Glucocorticoids then play a role in maintenance of chromaffin cells in postnatal life, this was only found recently, as previously it was thought that glucocorticoids were responsible entirely for the differentiation of neural crest cells into chromaffin, or adrenomedullary cells {{#pmid:23220335|PMID23220335}}.

===Developmental/adult function===
----
===Tissue and Organ structure===

====Normal Structure and Function of the Adrenal Medulla====

The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The medulla contains secretory cells called chromaffin cells, due to the agents they produce when oxidised, such as chromate. These cells secrete epinephrine and norepinephrine in response to various substances such as acetylcholine.

There are three types of cells in the adult adrenal medulla:
1) Epinephrine cells

2) Norepinephrine cells

3) Small granule-containing cells (SGCs)

These cells also produce various other peptides such as substance P and neurotensin. The adrenal medulla also contains presynaptic sympathetic ganglion cells. {{#pmid:1694230|PMID1694230}}

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus. {{#pmid:11215683|PMID11215683}}

====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses.

[[File:Dd.jpg|500px|thumb|right|Adult Adrenal Glands in situ]]
----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

Members of the SOX (SRY-Box) gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands.

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well.

[[File:Catecholamine_Synthesis.jpg|500px|thumb|right|Cascade of Catecholamine Synthesis]]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291442/
https://www.ncbi.nlm.nih.gov/pubmed/19396395

===Abnormalities/abnormal development===
----
===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

====Chromaffin cells (in rat models)====
There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells. The neural crest cells give rise to chromaffin cells of the adrenal medulla.

To study the formation process of the adrenal medulla in the embryonic period, we visualized chromaffin cells of rat embryos at 13 to 17 days of gestation using anti-tyrosine hydroxylase (TH) antiserum, and created three-dimensional images from serial tissue sections. Between 13 and 15 days of gestation, TH-positive cells (chromaffin cells) migrated from a group of TH-positive cells present dorsal to the adrenal primordium via the medial cranial end of the adrenal primordium into the adrenal primordium. At or after 16 days of gestation, the adrenal capsule was formed except on the ventral aspect of the cranial end of the adrenal gland, from which TH-positive cells penetrated into the adrenal gland.(Pubmed: 15240937)

Past research has reported that nueral crest cells
migrate into sympathetic ganglia and the adrenal cortex and almost completely convert t chromaffin cells by 19 days of gestation, forming the adrenal medulla. Since TH is used in this study as an indicator of chromaffin cells (adrenal medullary cells) is an enzyme involved in the early stage of the synthetic pathway of adrenaline and noradrenaline, the TH - positive cells observed in this study may include not only chromaffin cells but also sympathetic ganglion cells and SIF cells.
It was previously thught that when neural crest - derived cells migrated via the sympatheti chain gangli into the adrenal gland or preaortic ganglion, they took different pathways to the respective destination at the time of passage through the ganglia of the sympathetic trunk.
However, the reconstructed images in this study showed that the pathway of neural crest - deriveed cells from the ganglia of the sympathetic trunk to the adrenal medulla overlapped with the pathway to the preaortic ganglion. We speculate that neural crest cells use the same pathway to migrate to the ganglia of the sympathetic trunk, to the adrenal gland, and to the preaortic ganglion, this onclusion is good agreement of the suggestion by Ahoren.
Ahonen suggested that some neural crest cells continue migration from the chain ganglia to the lateral sides of aorta, where they form the perirenal ganglia and adrenal medulla, and finally to the ventral side of the aorta to form the preaortic sympathetic tissue. However, that report only showed the several transverse sections of the fetal trunk for the a demonstration of the migration route of neural crest cells. In this study, using three dimensional reconstructed images, we aimed to observe how TH-labeled chromaffin cells penetrate into the adrenal anlage to form the adrenal medulla and whether the migration route of TH - positive cells from the adrenal connects the preaortic sympathetic ganglia
(M.Yamato, R. Yanai, K. Arishima, 2004)

Prenatal adrenal gland development has been described in numerous published reports covering a wide variety of species, including the ox (Katznelson, 1966; Wrobel and Suss, 1999), sheep (Davies, 1950; Wintour et al., 1975; Upadhyay and Zamboni, 1982; Naaman‐Reperant and Durand, 1997; Grino, 2004), swine (Sokolov et al., 2006) and mouse (Waring, 1935; Ikeda et al., 1994; Sass, 1996; Nyska and Maronpot, 1999; Bland et al., 2003; Val et al., 2007). Adrenal gland development also has been extensively described for humans as well (Kolliker, 1879; Minot, 1892; Zuckerkandl, 1912; Wieman, 1920; Ikeda et al., 1981; Langlois et al., 2002; Hanley and Arit, 2006).

https://www.sciencedirect.com/science/article/pii/S0925477302004550
http://dev.biologists.org/content/develop/126/13/2935.full.pdf

===Current research (labs)===
----
The findings presented until now have focused on the mechanisms controlling migration along the dorsolateral path. In comparison, our understanding of the mechanisms controlling NCC migration along the ventral path are complicated by the fact that this population comprises multiple precursors that form different derivatives in distinct regions of the embryo. For example, ventrally migrating NCCs either stop within the sclerotome in close association with the neural tube to form neurons and glia of the sensory nervous system (i.e. the dorsal root ganglia [DRG]), while other NCCs continue to migrate further ventrally to form the autonomic nervous system (i.e. sympathetic ganglia and chromaffin cells of the adrenal gland)

Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/

===Glossary===
----
===Reference list===

2018 Group Project 1

2018-10-12T09:14:41Z

Z5113627: /* Related Anatomy */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===
[[User:Z5014972|Z5014972]] ([[User talk:Z5014972|talk]]) 12:47, 14 August 2018 (AEST)z5014972
good review article https://link.springer.com/article/10.1007%2Fs12022-009-9070-6
----

The neural crest of an embryo differentiates and migrates to form various components of the body. One of these tissues is the medulla of the adrenal gland which is involved in the production of adrenalin and noradrenalin. This project will comprehensively outline the history of neural crest research, the embryonic developmental time course, tissue and organ structure, molecular mechanisms, abnormalities, animal models and current research.

===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.
[[File:NC Location.jpg|left|450px|thumb|The neural crest]]

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniably lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Embryonic origins===
----
[[File:Trunk_NCC_migration.jpg|left|450px|thumb|Trunk NCC migration]]
The adrenal gland is made up of the adrenal cortex and adrenal medulla, which both have different embryonic origins. The adrenal medulla arises from the neural crest tissue, found near the level of the coeliac plexus & sympathetic ganglion at somites 18-24 {{#pmid:16124976|PMID16124976}}. Specifically, this neural crest tissue comes from the trunk neural crest cells (see above figure to determine the approximate location in an embryo) <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
The trunk neural crest coordinates the development of the endocrine system, secretory cells, the peripheral nervous system and, to some degree, skeletal development, as well as innervation of the intestine {{#pmid: 28287247|PMID 28287247}}. The trunk neural cells arise caudally, undergo an epithelial to mesenchymal transition and follow three migratory pathways {{#pmid:20399766|PMID20399766}}.
[[File:Differentiation_of_NCC.jpg|left|580px|thumb|Differentiation of chromaffin cells]]
- A dorsolateral pathway (between ectoderm and somites), these become melanocytes, travel up to the point of the dermis and become a major part of the hair follicles and skin <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.
- A ventrolateral pathway (through the somites)
- A ventromedial pathway (between neural tube and posterior schlerotome){{#pmid:20399766|PMID20399766}}.

Migration of neural crest cells from the sympathetic ganglion is what leads to the development of the adrenal medulla. In week 8 of development, immature cells called neuroblasts migrate through to the inner portion of the medulla, where they become the adrenal medulla {{#pmid:19683477|PMID19683477}}. Chromaffin cells are neuroendocrine cells and are found in the sympathetic ganglia and make up the majority of the adrenal medulla{{#pmid:19683477|PMID19683477}}. They synthesise and release a range of hormones in the body and arise from the temporary neural crest. The term chromaffin was inspired by the staining capacity of these cells when they came into contact with chrome salts. They make, store, export and use catecholamines, responsible for making noradrenaline and originate at the caudal region of somites 18-24 of the neural crest, also known as the adrenomedullary region {{#pmid:19683477|PMID19683477}}.

For cells to leave the neural crest and begin their migration, certain conditions need to be met, that is, the cells need to be loosely connected, their tight junctions becoming relaxed, initiated by "Slug protein" and a loss of N-Cadherin which also leads to the loosening of these junctions. The surrounding matrix as well as chemotactic and stem cell factors of the neural tube are then what dictates how the neural crest cells move, some proteins stopping their migration to that area and others encouraging the movement <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. After splitting apart, the first neural crest cells move ventrally and pass into the spaces between the somites and then, through the anterior portions of each segment until they arrive at the para-aortic sites, where they become the cells of the sympathetic ganglia and the adrenal medulla {{#pmid:19683477|PMID19683477}}. BMP-4 (bone morphogenetic protein 4) then acts on these neural crest cells, preventing them from becoming cells that have a neural function and causing them to become chromaffin cells at the adrenal medulla. Glucocorticoids then play a role in maintenance of chromaffin cells in postnatal life, this was only found recently, as previously it was thought that glucocorticoids were responsible entirely for the differentiation of neural crest cells into chromaffin, or adrenomedullary cells {{#pmid:23220335|PMID23220335}}.

===Developmental/adult function===
----
===Tissue and Organ structure===

====Normal Structure and Function of the Adrenal Medulla====

The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The medulla contains secretory cells called chromaffin cells, due to the agents they produce when oxidised, such as chromate. These cells secrete epinephrine and norepinephrine in response to various substances such as acetylcholine.

There are three types of cells in the adult adrenal medulla:
1) Epinephrine cells

2) Norepinephrine cells

3) Small granule-containing cells (SGCs)

These cells also produce various other peptides such as substance P and neurotensin. The adrenal medulla also contains presynaptic sympathetic ganglion cells. {{#pmid:1694230|PMID1694230}}

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus. {{#pmid11215683|PMID11215683}}

====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses.

[[File:Dd.jpg|500px|thumb|right|Adult Adrenal Glands in situ]]
----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

Members of the SOX (SRY-Box) gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands.

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well.

[[File:Catecholamine_Synthesis.jpg|500px|thumb|right|Cascade of Catecholamine Synthesis]]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291442/
https://www.ncbi.nlm.nih.gov/pubmed/19396395

===Abnormalities/abnormal development===
----
===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

====Chromaffin cells (in rat models)====
There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells. The neural crest cells give rise to chromaffin cells of the adrenal medulla.

To study the formation process of the adrenal medulla in the embryonic period, we visualized chromaffin cells of rat embryos at 13 to 17 days of gestation using anti-tyrosine hydroxylase (TH) antiserum, and created three-dimensional images from serial tissue sections. Between 13 and 15 days of gestation, TH-positive cells (chromaffin cells) migrated from a group of TH-positive cells present dorsal to the adrenal primordium via the medial cranial end of the adrenal primordium into the adrenal primordium. At or after 16 days of gestation, the adrenal capsule was formed except on the ventral aspect of the cranial end of the adrenal gland, from which TH-positive cells penetrated into the adrenal gland.(Pubmed: 15240937)

Past research has reported that nueral crest cells
migrate into sympathetic ganglia and the adrenal cortex and almost completely convert t chromaffin cells by 19 days of gestation, forming the adrenal medulla. Since TH is used in this study as an indicator of chromaffin cells (adrenal medullary cells) is an enzyme involved in the early stage of the synthetic pathway of adrenaline and noradrenaline, the TH - positive cells observed in this study may include not only chromaffin cells but also sympathetic ganglion cells and SIF cells.
It was previously thught that when neural crest - derived cells migrated via the sympatheti chain gangli into the adrenal gland or preaortic ganglion, they took different pathways to the respective destination at the time of passage through the ganglia of the sympathetic trunk.
However, the reconstructed images in this study showed that the pathway of neural crest - deriveed cells from the ganglia of the sympathetic trunk to the adrenal medulla overlapped with the pathway to the preaortic ganglion. We speculate that neural crest cells use the same pathway to migrate to the ganglia of the sympathetic trunk, to the adrenal gland, and to the preaortic ganglion, this onclusion is good agreement of the suggestion by Ahoren.
Ahonen suggested that some neural crest cells continue migration from the chain ganglia to the lateral sides of aorta, where they form the perirenal ganglia and adrenal medulla, and finally to the ventral side of the aorta to form the preaortic sympathetic tissue. However, that report only showed the several transverse sections of the fetal trunk for the a demonstration of the migration route of neural crest cells. In this study, using three dimensional reconstructed images, we aimed to observe how TH-labeled chromaffin cells penetrate into the adrenal anlage to form the adrenal medulla and whether the migration route of TH - positive cells from the adrenal connects the preaortic sympathetic ganglia
(M.Yamato, R. Yanai, K. Arishima, 2004)

Prenatal adrenal gland development has been described in numerous published reports covering a wide variety of species, including the ox (Katznelson, 1966; Wrobel and Suss, 1999), sheep (Davies, 1950; Wintour et al., 1975; Upadhyay and Zamboni, 1982; Naaman‐Reperant and Durand, 1997; Grino, 2004), swine (Sokolov et al., 2006) and mouse (Waring, 1935; Ikeda et al., 1994; Sass, 1996; Nyska and Maronpot, 1999; Bland et al., 2003; Val et al., 2007). Adrenal gland development also has been extensively described for humans as well (Kolliker, 1879; Minot, 1892; Zuckerkandl, 1912; Wieman, 1920; Ikeda et al., 1981; Langlois et al., 2002; Hanley and Arit, 2006).

https://www.sciencedirect.com/science/article/pii/S0925477302004550
http://dev.biologists.org/content/develop/126/13/2935.full.pdf

===Current research (labs)===
----
The findings presented until now have focused on the mechanisms controlling migration along the dorsolateral path. In comparison, our understanding of the mechanisms controlling NCC migration along the ventral path are complicated by the fact that this population comprises multiple precursors that form different derivatives in distinct regions of the embryo. For example, ventrally migrating NCCs either stop within the sclerotome in close association with the neural tube to form neurons and glia of the sensory nervous system (i.e. the dorsal root ganglia [DRG]), while other NCCs continue to migrate further ventrally to form the autonomic nervous system (i.e. sympathetic ganglia and chromaffin cells of the adrenal gland)

Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/

===Glossary===
----
===Reference list===

2018 Group Project 1

2018-10-08T15:21:50Z

Z5113627: /* Tissue and Organ structure */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===
[[User:Z5014972|Z5014972]] ([[User talk:Z5014972|talk]]) 12:47, 14 August 2018 (AEST)z5014972
good review article https://link.springer.com/article/10.1007%2Fs12022-009-9070-6
----

The neural crest of an embryo differentiates and migrates to form various components of the body. One of these tissues is the medulla of the adrenal gland which is involved in the production of adrenalin and noradrenalin. This project will comprehensively outline the history of neural crest research, the embryonic developmental time course, tissue and organ structure, molecular mechanisms, abnormalities, animal models and current research.

===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.
[[File:NC Location.jpg|left|450px|thumb|The neural crest]]

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniable lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Embryonic origins===
----
https://www.ncbi.nlm.nih.gov/books/NBK10065/

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Developmental/adult function===
----
===Tissue and Organ structure===

====Normal Structure and Function of the Adrenal Medulla====

The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The medulla contains secretory cells called chromaffin cells, due to the agents they produce when oxidised, such as chromate. These cells secrete epinephrine and norepinephrine in response to various substances such as acetylcholine.

There are three types of cells in the adult adrenal medulla:
1) Epinephrine cells

2) Norepinephrine cells

3) Small granule-containing cells (SGCs)

These cells also produce various other peptides such as substance P and neurotensin. The adrenal medulla also contains presynaptic sympathetic ganglion cells. {{#pmid:1694230|PMID1694230}}

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus.

====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses.

[[File:Dd.jpg|500px|thumb|right|Adult Adrenal Glands in situ]]
----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

Members of the SOX (SRY-Box) gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands.

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well.

[[File:Catecholamine_Synthesis.jpg|500px|thumb|right|Cascade of Catecholamine Synthesis]]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291442/
https://www.ncbi.nlm.nih.gov/pubmed/19396395

===Abnormalities/abnormal development===
----
===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells. The neural crest cells give rise to chromaffin cells of the adrenal medulla.
Ahonen suggested that some neural crest cells continue migration from the chain ganglia to the lateral sides of aorta, where they form the perirenal ganglia and adrenal medulla, and finally to the ventral side of the aorta to form the preaortic sympathetic tissue. However, that report only showed the several transverse sections of the fetal trunk for the a demonstration of the migration route of neural crest cells. In this study, using three dimensional reconstructed images, we aimed to observe how TH-labeled chromaffin cells penetrate into the adrenal anlage to form the adrenal medulla and whether the migration route of TH - positive cells from the adrenal connects the preaortic sympathetic ganglia
(M.Yamato, R. Yanai, K. Arishima, 2004)

Prenatal adrenal gland development has been described in numerous published reports covering a wide variety of species, including the ox (Katznelson, 1966; Wrobel and Suss, 1999), sheep (Davies, 1950; Wintour et al., 1975; Upadhyay and Zamboni, 1982; Naaman‐Reperant and Durand, 1997; Grino, 2004), swine (Sokolov et al., 2006) and mouse (Waring, 1935; Ikeda et al., 1994; Sass, 1996; Nyska and Maronpot, 1999; Bland et al., 2003; Val et al., 2007). Adrenal gland development also has been extensively described for humans as well (Kolliker, 1879; Minot, 1892; Zuckerkandl, 1912; Wieman, 1920; Ikeda et al., 1981; Langlois et al., 2002; Hanley and Arit, 2006).

https://www.sciencedirect.com/science/article/pii/S0925477302004550
http://dev.biologists.org/content/develop/126/13/2935.full.pdf

===Current research (labs)===
----
The findings presented until now have focused on the mechanisms controlling migration along the dorsolateral path. In comparison, our understanding of the mechanisms controlling NCC migration along the ventral path are complicated by the fact that this population comprises multiple precursors that form different derivatives in distinct regions of the embryo. For example, ventrally migrating NCCs either stop within the sclerotome in close association with the neural tube to form neurons and glia of the sensory nervous system (i.e. the dorsal root ganglia [DRG]), while other NCCs continue to migrate further ventrally to form the autonomic nervous system (i.e. sympathetic ganglia and chromaffin cells of the adrenal gland)

Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/

===Glossary===
----
===Reference list===

2018 Group Project 1

2018-10-08T15:18:11Z

Z5113627: /* Normal Structure and Function of the Adrenal Medulla */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===
[[User:Z5014972|Z5014972]] ([[User talk:Z5014972|talk]]) 12:47, 14 August 2018 (AEST)z5014972
good review article https://link.springer.com/article/10.1007%2Fs12022-009-9070-6
----

The neural crest of an embryo differentiates and migrates to form various components of the body. One of these tissues is the medulla of the adrenal gland which is involved in the production of adrenalin and noradrenalin. This project will comprehensively outline the history of neural crest research, the embryonic developmental time course, tissue and organ structure, molecular mechanisms, abnormalities, animal models and current research.

===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.
[[File:NC Location.jpg|left|450px|thumb|The neural crest]]

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniable lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Embryonic origins===
----
https://www.ncbi.nlm.nih.gov/books/NBK10065/

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Developmental/adult function===
----
===Tissue and Organ structure===

====Normal Structure and Function of the Adrenal Medulla====

The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The medulla contains secretory cells called chromaffin cells, due to the agents they produce when oxidised, such as chromate. These cells secrete epinephrine and norepinephrine in response to various substances such as acetylcholine.

There are three types of cells in the adult adrenal medulla:
1) Epinephrine cells

2) Norepinephrine cells

3) Small granule-containing cells (SGCs)

These cells also produce various other peptides such as substance P and neurotensin. The adrenal medulla also contains presynaptic sympathetic ganglion cells.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus.

====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses.

[[File:Dd.jpg|500px|thumb|right|Adult Adrenal Glands in situ]]
----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

Members of the SOX (SRY-Box) gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands.

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well.

[[File:Catecholamine_Synthesis.jpg|500px|thumb|right|Cascade of Catecholamine Synthesis]]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291442/
https://www.ncbi.nlm.nih.gov/pubmed/19396395

===Abnormalities/abnormal development===
----
===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells. The neural crest cells give rise to chromaffin cells of the adrenal medulla.
Ahonen suggested that some neural crest cells continue migration from the chain ganglia to the lateral sides of aorta, where they form the perirenal ganglia and adrenal medulla, and finally to the ventral side of the aorta to form the preaortic sympathetic tissue. However, that report only showed the several transverse sections of the fetal trunk for the a demonstration of the migration route of neural crest cells. In this study, using three dimensional reconstructed images, we aimed to observe how TH-labeled chromaffin cells penetrate into the adrenal anlage to form the adrenal medulla and whether the migration route of TH - positive cells from the adrenal connects the preaortic sympathetic ganglia
(M.Yamato, R. Yanai, K. Arishima, 2004)

Prenatal adrenal gland development has been described in numerous published reports covering a wide variety of species, including the ox (Katznelson, 1966; Wrobel and Suss, 1999), sheep (Davies, 1950; Wintour et al., 1975; Upadhyay and Zamboni, 1982; Naaman‐Reperant and Durand, 1997; Grino, 2004), swine (Sokolov et al., 2006) and mouse (Waring, 1935; Ikeda et al., 1994; Sass, 1996; Nyska and Maronpot, 1999; Bland et al., 2003; Val et al., 2007). Adrenal gland development also has been extensively described for humans as well (Kolliker, 1879; Minot, 1892; Zuckerkandl, 1912; Wieman, 1920; Ikeda et al., 1981; Langlois et al., 2002; Hanley and Arit, 2006).

https://www.sciencedirect.com/science/article/pii/S0925477302004550
http://dev.biologists.org/content/develop/126/13/2935.full.pdf

===Current research (labs)===
----
The findings presented until now have focused on the mechanisms controlling migration along the dorsolateral path. In comparison, our understanding of the mechanisms controlling NCC migration along the ventral path are complicated by the fact that this population comprises multiple precursors that form different derivatives in distinct regions of the embryo. For example, ventrally migrating NCCs either stop within the sclerotome in close association with the neural tube to form neurons and glia of the sensory nervous system (i.e. the dorsal root ganglia [DRG]), while other NCCs continue to migrate further ventrally to form the autonomic nervous system (i.e. sympathetic ganglia and chromaffin cells of the adrenal gland)

Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/

===Glossary===
----
===Reference list===

2018 Group Project 1

2018-10-08T11:46:32Z

Z5113627: /* Role of Adrenal Medulla in the Neonate and Adult */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===
[[User:Z5014972|Z5014972]] ([[User talk:Z5014972|talk]]) 12:47, 14 August 2018 (AEST)z5014972
good review article https://link.springer.com/article/10.1007%2Fs12022-009-9070-6
----
===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.
[[File:NC Location.jpg|left|450px|thumb|The neural crest]]

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniable lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Embryonic origins===
----
https://www.ncbi.nlm.nih.gov/books/NBK10065/

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Developmental/adult function===
----
===Tissue and Organ structure===

====Normal Structure and Function of the Adrenal Medulla====

The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The medulla contains secretory cells called chromaffin cells, due to the agents they produce when oxidised, such as chromate. These cells secrete epinephrine and norepinephrine in response to various substances such as acetylcholine.

There are three types of cells in the adult adrenal medulla:
1) Epinephrine cells
2) Norepinephrine cells
3) Small granule-containing cells (SGCs)
These cells also produce various other peptides such as substance P and neurotensin. The adrenal medulla also contains presynaptic sympathetic ganglion cells.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus.

====Role of the Adrenal Medulla====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses.

[[File:Dd.jpg|500px|thumb|right|Adult Adrenal Glands in situ]]
----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

Members of the SOX (SRY-Box) gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands.

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well.

[[File:Catecholamine_Synthesis.jpg|500px|thumb|right|Cascade of Catecholamine Synthesis]]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291442/
https://www.ncbi.nlm.nih.gov/pubmed/19396395

===Abnormalities/abnormal development===
----
===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells. The neural crest cells give rise to chromaffin cells of the adrenal medulla.
Ahonen suggested that some neural crest cells continue migration from the chain ganglia to the lateral sides of aorta, where they form the perirenal ganglia and adrenal medulla, and finally to the ventral side of the aorta to form the preaortic sympathetic tissue. However, that report only showed the several transverse sections of the fetal trunk for the a demonstration of the migration route of neural crest cells. In this study, using three dimensional reconstructed images, we aimed to observe how TH-labeled chromaffin cells penetrate into the adrenal anlage to form the adrenal medulla and whether the migration route of TH - positive cells from the adrenal connects the preaortic sympathetic ganglia
(M.Yamato, R. Yanai, K. Arishima, 2004)

Prenatal adrenal gland development has been described in numerous published reports covering a wide variety of species, including the ox (Katznelson, 1966; Wrobel and Suss, 1999), sheep (Davies, 1950; Wintour et al., 1975; Upadhyay and Zamboni, 1982; Naaman‐Reperant and Durand, 1997; Grino, 2004), swine (Sokolov et al., 2006) and mouse (Waring, 1935; Ikeda et al., 1994; Sass, 1996; Nyska and Maronpot, 1999; Bland et al., 2003; Val et al., 2007). Adrenal gland development also has been extensively described for humans as well (Kolliker, 1879; Minot, 1892; Zuckerkandl, 1912; Wieman, 1920; Ikeda et al., 1981; Langlois et al., 2002; Hanley and Arit, 2006).

https://www.sciencedirect.com/science/article/pii/S0925477302004550
http://dev.biologists.org/content/develop/126/13/2935.full.pdf

===Current research (labs)===
----
The findings presented until now have focused on the mechanisms controlling migration along the dorsolateral path. In comparison, our understanding of the mechanisms controlling NCC migration along the ventral path are complicated by the fact that this population comprises multiple precursors that form different derivatives in distinct regions of the embryo. For example, ventrally migrating NCCs either stop within the sclerotome in close association with the neural tube to form neurons and glia of the sensory nervous system (i.e. the dorsal root ganglia [DRG]), while other NCCs continue to migrate further ventrally to form the autonomic nervous system (i.e. sympathetic ganglia and chromaffin cells of the adrenal gland)

Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/

===Glossary===
----
===Reference list===

2018 Group Project 1

2018-10-08T11:10:19Z

Z5113627: /* Role of Adrenal Medulla in the Neonate and Adult */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===
[[User:Z5014972|Z5014972]] ([[User talk:Z5014972|talk]]) 12:47, 14 August 2018 (AEST)z5014972
good review article https://link.springer.com/article/10.1007%2Fs12022-009-9070-6
----
===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.
[[File:NC Location.jpg|left|450px|thumb|The neural crest]]

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniable lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Embryonic origins===
----
https://www.ncbi.nlm.nih.gov/books/NBK10065/

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Developmental/adult function===
----
===Tissue and Organ structure===

====Normal Structure and Function of the Adrenal Medulla====

The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The medulla contains secretory cells called chromaffin cells, due to the agents they produce when oxidised, such as chromate. These cells secrete epinephrine and norepinephrine in response to various substances such as acetylcholine.

There are three types of cells in the adult adrenal medulla:
1) Epinephrine cells
2) Norepinephrine cells
3) Small granule-containing cells (SGCs)
These cells also produce various other peptides such as substance P and neurotensin. The adrenal medulla also contains presynaptic sympathetic ganglion cells.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus.

====Role of Adrenal Medulla in the Neonate and Adult====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses.

[[File:Dd.jpg|500px|thumb|right|Adult Adrenal Glands in situ]]
----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

Members of the SOX (SRY-Box) gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands.

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well.

[[File:Catecholamine_Synthesis.jpg|500px|thumb|right|Cascade of Catecholamine Synthesis]]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291442/
https://www.ncbi.nlm.nih.gov/pubmed/19396395

===Abnormalities/abnormal development===
----
===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells. The neural crest cells give rise to chromaffin cells of the adrenal medulla.
Ahonen suggested that some neural crest cells continue migration from the chain ganglia to the lateral sides of aorta, where they form the perirenal ganglia and adrenal medulla, and finally to the ventral side of the aorta to form the preaortic sympathetic tissue. However, that report only showed the several transverse sections of the fetal trunk for the a demonstration of the migration route of neural crest cells. In this study, using three dimensional reconstructed images, we aimed to observe how TH-labeled chromaffin cells penetrate into the adrenal anlage to form the adrenal medulla and whether the migration route of TH - positive cells from the adrenal connects the preaortic sympathetic ganglia
(M.Yamato, R. Yanai, K. Arishima, 2004)

Prenatal adrenal gland development has been described in numerous published reports covering a wide variety of species, including the ox (Katznelson, 1966; Wrobel and Suss, 1999), sheep (Davies, 1950; Wintour et al., 1975; Upadhyay and Zamboni, 1982; Naaman‐Reperant and Durand, 1997; Grino, 2004), swine (Sokolov et al., 2006) and mouse (Waring, 1935; Ikeda et al., 1994; Sass, 1996; Nyska and Maronpot, 1999; Bland et al., 2003; Val et al., 2007). Adrenal gland development also has been extensively described for humans as well (Kolliker, 1879; Minot, 1892; Zuckerkandl, 1912; Wieman, 1920; Ikeda et al., 1981; Langlois et al., 2002; Hanley and Arit, 2006).

https://www.sciencedirect.com/science/article/pii/S0925477302004550
http://dev.biologists.org/content/develop/126/13/2935.full.pdf

===Current research (labs)===
----
The findings presented until now have focused on the mechanisms controlling migration along the dorsolateral path. In comparison, our understanding of the mechanisms controlling NCC migration along the ventral path are complicated by the fact that this population comprises multiple precursors that form different derivatives in distinct regions of the embryo. For example, ventrally migrating NCCs either stop within the sclerotome in close association with the neural tube to form neurons and glia of the sensory nervous system (i.e. the dorsal root ganglia [DRG]), while other NCCs continue to migrate further ventrally to form the autonomic nervous system (i.e. sympathetic ganglia and chromaffin cells of the adrenal gland)

Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/

===Glossary===
----
===Reference list===

2018 Group Project 1

2018-10-08T11:09:55Z

Z5113627: /* Tissue and Organ structure */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===
[[User:Z5014972|Z5014972]] ([[User talk:Z5014972|talk]]) 12:47, 14 August 2018 (AEST)z5014972
good review article https://link.springer.com/article/10.1007%2Fs12022-009-9070-6
----
===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.
[[File:NC Location.jpg|left|450px|thumb|The neural crest]]

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniable lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Embryonic origins===
----
https://www.ncbi.nlm.nih.gov/books/NBK10065/

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Developmental/adult function===
----
===Tissue and Organ structure===

====Normal Structure and Function of the Adrenal Medulla====

The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The medulla contains secretory cells called chromaffin cells, due to the agents they produce when oxidised, such as chromate. These cells secrete epinephrine and norepinephrine in response to various substances such as acetylcholine.

There are three types of cells in the adult adrenal medulla:
1) Epinephrine cells
2) Norepinephrine cells
3) Small granule-containing cells (SGCs)
These cells also produce various other peptides such as substance P and neurotensin. The adrenal medulla also contains presynaptic sympathetic ganglion cells.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus.

====Role of Adrenal Medulla in the Neonate and Adult====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

>Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

>Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses.

[[File:Dd.jpg|500px|thumb|right|Adult Adrenal Glands in situ]]
----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

Members of the SOX (SRY-Box) gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands.

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well.

[[File:Catecholamine_Synthesis.jpg|500px|thumb|right|Cascade of Catecholamine Synthesis]]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291442/
https://www.ncbi.nlm.nih.gov/pubmed/19396395

===Abnormalities/abnormal development===
----
===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells. The neural crest cells give rise to chromaffin cells of the adrenal medulla.
Ahonen suggested that some neural crest cells continue migration from the chain ganglia to the lateral sides of aorta, where they form the perirenal ganglia and adrenal medulla, and finally to the ventral side of the aorta to form the preaortic sympathetic tissue. However, that report only showed the several transverse sections of the fetal trunk for the a demonstration of the migration route of neural crest cells. In this study, using three dimensional reconstructed images, we aimed to observe how TH-labeled chromaffin cells penetrate into the adrenal anlage to form the adrenal medulla and whether the migration route of TH - positive cells from the adrenal connects the preaortic sympathetic ganglia
(M.Yamato, R. Yanai, K. Arishima, 2004)

Prenatal adrenal gland development has been described in numerous published reports covering a wide variety of species, including the ox (Katznelson, 1966; Wrobel and Suss, 1999), sheep (Davies, 1950; Wintour et al., 1975; Upadhyay and Zamboni, 1982; Naaman‐Reperant and Durand, 1997; Grino, 2004), swine (Sokolov et al., 2006) and mouse (Waring, 1935; Ikeda et al., 1994; Sass, 1996; Nyska and Maronpot, 1999; Bland et al., 2003; Val et al., 2007). Adrenal gland development also has been extensively described for humans as well (Kolliker, 1879; Minot, 1892; Zuckerkandl, 1912; Wieman, 1920; Ikeda et al., 1981; Langlois et al., 2002; Hanley and Arit, 2006).

https://www.sciencedirect.com/science/article/pii/S0925477302004550
http://dev.biologists.org/content/develop/126/13/2935.full.pdf

===Current research (labs)===
----
The findings presented until now have focused on the mechanisms controlling migration along the dorsolateral path. In comparison, our understanding of the mechanisms controlling NCC migration along the ventral path are complicated by the fact that this population comprises multiple precursors that form different derivatives in distinct regions of the embryo. For example, ventrally migrating NCCs either stop within the sclerotome in close association with the neural tube to form neurons and glia of the sensory nervous system (i.e. the dorsal root ganglia [DRG]), while other NCCs continue to migrate further ventrally to form the autonomic nervous system (i.e. sympathetic ganglia and chromaffin cells of the adrenal gland)

Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/

===Glossary===
----
===Reference list===

2018 Group Project 1

2018-10-08T11:09:20Z

Z5113627: /* Tissue/organ structure */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===
[[User:Z5014972|Z5014972]] ([[User talk:Z5014972|talk]]) 12:47, 14 August 2018 (AEST)z5014972
good review article https://link.springer.com/article/10.1007%2Fs12022-009-9070-6
----
===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.
[[File:NC Location.jpg|left|450px|thumb|The neural crest]]

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniable lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Embryonic origins===
----
https://www.ncbi.nlm.nih.gov/books/NBK10065/

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Developmental/adult function===
----
===Tissue and Organ structure===

====Normal Structure and Function of the Adrenal Medulla====

The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The medulla contains secretory cells called chromaffin cells, due to the agents they produce when oxidised, such as chromate. These cells secrete epinephrine and norepinephrine in response to various substances such as acetylcholine.

There are three types of cells in the adult adrenal medulla:
1) Epinephrine cells
2) Norepinephrine cells
3) Small granule-containing cells (SGCs)
These cells also produce various other peptides such as substance P and neurotensin. The adrenal medulla also contains presynaptic sympathetic ganglion cells.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus.

====Role of Adrenal Medulla in the Neonate and Adult====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

>Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

>Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses.

[[File:Dd.jpg|500px|thumb|right|Adult Adrenal Glands in situ]]
----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

Members of the SOX (SRY-Box) gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands.

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well.

[[File:Catecholamine_Synthesis.jpg|500px|thumb|right|Cascade of Catecholamine Synthesis]]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291442/
https://www.ncbi.nlm.nih.gov/pubmed/19396395

===Abnormalities/abnormal development===
----
===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells. The neural crest cells give rise to chromaffin cells of the adrenal medulla.
Ahonen suggested that some neural crest cells continue migration from the chain ganglia to the lateral sides of aorta, where they form the perirenal ganglia and adrenal medulla, and finally to the ventral side of the aorta to form the preaortic sympathetic tissue. However, that report only showed the several transverse sections of the fetal trunk for the a demonstration of the migration route of neural crest cells. In this study, using three dimensional reconstructed images, we aimed to observe how TH-labeled chromaffin cells penetrate into the adrenal anlage to form the adrenal medulla and whether the migration route of TH - positive cells from the adrenal connects the preaortic sympathetic ganglia
(M.Yamato, R. Yanai, K. Arishima, 2004)

Prenatal adrenal gland development has been described in numerous published reports covering a wide variety of species, including the ox (Katznelson, 1966; Wrobel and Suss, 1999), sheep (Davies, 1950; Wintour et al., 1975; Upadhyay and Zamboni, 1982; Naaman‐Reperant and Durand, 1997; Grino, 2004), swine (Sokolov et al., 2006) and mouse (Waring, 1935; Ikeda et al., 1994; Sass, 1996; Nyska and Maronpot, 1999; Bland et al., 2003; Val et al., 2007). Adrenal gland development also has been extensively described for humans as well (Kolliker, 1879; Minot, 1892; Zuckerkandl, 1912; Wieman, 1920; Ikeda et al., 1981; Langlois et al., 2002; Hanley and Arit, 2006).

https://www.sciencedirect.com/science/article/pii/S0925477302004550
http://dev.biologists.org/content/develop/126/13/2935.full.pdf

===Current research (labs)===
----
The findings presented until now have focused on the mechanisms controlling migration along the dorsolateral path. In comparison, our understanding of the mechanisms controlling NCC migration along the ventral path are complicated by the fact that this population comprises multiple precursors that form different derivatives in distinct regions of the embryo. For example, ventrally migrating NCCs either stop within the sclerotome in close association with the neural tube to form neurons and glia of the sensory nervous system (i.e. the dorsal root ganglia [DRG]), while other NCCs continue to migrate further ventrally to form the autonomic nervous system (i.e. sympathetic ganglia and chromaffin cells of the adrenal gland)

Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/

===Glossary===
----
===Reference list===

2018 Group Project 1

2018-10-08T11:08:15Z

Z5113627: /* Role of Adrenal Medulla in the Neonate and Adult */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===
[[User:Z5014972|Z5014972]] ([[User talk:Z5014972|talk]]) 12:47, 14 August 2018 (AEST)z5014972
good review article https://link.springer.com/article/10.1007%2Fs12022-009-9070-6
----
===History===
----
'''Describing the neural crest'''
[[File:Wilhelm_His_History_Wilhelm.jpeg|left|230px|thumb|Wilhelm His]]
The "neural crest" is a structure in the embryo and is the junction between the neural and epidermal ectoderm. It is exclusive to vertebrates and forms a range of structures{{#pmid:22230617|PMID22230617}}. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. {{#pmid:19179766|PMID19179766}}.
[[File:NC Location.jpg|left|450px|thumb|The neural crest]]

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently of one another.In the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many{{#pmid:22820859|PMID22820859}}.

This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding created brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest does indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''
In the 1960s, the migration patterns of neural crest cells were studied in avian embryos (birds). This was a shift from studying the embryos of amphibians. This was inspired by studies conducted in the 1960s on neural crest cells migrating from the brain and spinal cord, known as trunk and cranial neural crest cells {{#pmid:19179766|PMID19179766}}. The cranial neural crest eventually becomes the bones, cartilage and connective tissues forming the foundation of the face, ears and teeth. The trunk neural crest cells can either become melanocytes or can migrate into sclerotomes which are later contributors to the cartilage of the spine and the dorsal root ganglia {{#pmid:22820859|PMID22820859}}. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. In the 1970s many detailed maps signifying the pathways of many of the neural crest cells appeared as well as an understanding that the environment in which the neural crest cells are found plays a major role in their final development as well as the occurrences of abnormalities in the fetus {{#pmid:19179766|PMID19179766}}.

'''1980s - 21st century'''
[[File:Regions_of_NC_Cells.jpg|left|Neural crest regions|thumb]]
From the 1980s-1990s, the causative agent of organ transformation from one to another (homeotic patterning), as well as the Hox genes which regulate the axis of most symmetrical animal embryos were founded and studied. The neural crest, which previously was divided into the cranial and trunk regions, was now further divided into the vagal and sacral neural crest, the cardiac neural crest and the cephalic neural crest {{#pmid:19179766|PMID19179766}}. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage{{#pmid:19179766|PMID19179766}}. This is important for the structure of the heart as well as its overall function, enabling it to move blood around the body efficiently as well as keep pulmonary and aortic circulation separated <ref name=Gilbert2000>Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. The Neural Crest. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10065/</ref>.

Today, knowledge of the neural crest cells, their migration patterns, modes of differentiation, derivatives and apoptosis (cell death) are being studied extensively. This is being done on a comparative basis between different organisms, to add further evidence for evolution {{#pmid:19179766|PMID19179766}}. The neural crest is definitely forging a "crest" between the fields of developmental and evolutionary biology, as it is a structure '''shared exclusively by all vertebrates'''. Invertebrates do not derive their specialised cells from the neural crest as they do not have one, rather, they derive these from the endomesoderm {{#pmid:22230617|PMID22230617}}.

'''Future directions'''

Since its discovery by His, the neural crest field has made great progress, from studies performed on the structure, to analysis of the molecules and whether certain aspects of the neural crest are specific to a single species of organism, or to all vertebrates collectively. Future work on the cranial neural crest needs to be done as well as identifying and categorising the networks responsible for the proliferation and death of cells, as well as how the cells move and migrate, as well as the gene regulatory networks (GRNs) that regulate the synthesis of proteins. Advances in technology will undeniable lead us to more answers on the subject {{#pmid:22230617|PMID22230617}}.

===Embryonic origins===
----
https://www.ncbi.nlm.nih.gov/books/NBK10065/

===Developmental time course===
----

[[File:Adrenal_Medulla_Developmental_Timeline.jpg|right|thumb|500px]]

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Developmental/adult function===
----
===Tissue/organ structure===

====Normal Structure and Function of the Adrenal Medulla====

The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The medulla contains secretory cells called chromaffin cells, due to the agents they produce when oxidised, such as chromate. These cells secrete epinephrine and norepinephrine in response to various substances such as acetylcholine.

There are three types of cells in the adult adrenal medulla:
1) Epinephrine cells
2) Norepinephrine cells
3) Small granule-containing cells (SGCs)
These cells also produce various other peptides such as substance P and neurotensin. The adrenal medulla also contains presynaptic sympathetic ganglion cells.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus.

[[File:Dd.jpg|500px|thumb|right|Adult Adrenal Glands in situ]]
----

===Molecular mechanisms/factors/genes===
----

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

Members of the SOX (SRY-Box) gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands.

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well.

[[File:Catecholamine_Synthesis.jpg|500px|thumb|right|Cascade of Catecholamine Synthesis]]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291442/
https://www.ncbi.nlm.nih.gov/pubmed/19396395

===Abnormalities/abnormal development===
----
===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

There has been extensive research conducted into the adrenal chromaffin cells and their embryological developments. As explained above nueral crest cells are pluripotent meaning they are able to differentiate into multiple different cells. The neural crest cells give rise to chromaffin cells of the adrenal medulla.
Ahonen suggested that some neural crest cells continue migration from the chain ganglia to the lateral sides of aorta, where they form the perirenal ganglia and adrenal medulla, and finally to the ventral side of the aorta to form the preaortic sympathetic tissue. However, that report only showed the several transverse sections of the fetal trunk for the a demonstration of the migration route of neural crest cells. In this study, using three dimensional reconstructed images, we aimed to observe how TH-labeled chromaffin cells penetrate into the adrenal anlage to form the adrenal medulla and whether the migration route of TH - positive cells from the adrenal connects the preaortic sympathetic ganglia
(M.Yamato, R. Yanai, K. Arishima, 2004)

Prenatal adrenal gland development has been described in numerous published reports covering a wide variety of species, including the ox (Katznelson, 1966; Wrobel and Suss, 1999), sheep (Davies, 1950; Wintour et al., 1975; Upadhyay and Zamboni, 1982; Naaman‐Reperant and Durand, 1997; Grino, 2004), swine (Sokolov et al., 2006) and mouse (Waring, 1935; Ikeda et al., 1994; Sass, 1996; Nyska and Maronpot, 1999; Bland et al., 2003; Val et al., 2007). Adrenal gland development also has been extensively described for humans as well (Kolliker, 1879; Minot, 1892; Zuckerkandl, 1912; Wieman, 1920; Ikeda et al., 1981; Langlois et al., 2002; Hanley and Arit, 2006).

https://www.sciencedirect.com/science/article/pii/S0925477302004550
http://dev.biologists.org/content/develop/126/13/2935.full.pdf

===Current research (labs)===
----
The findings presented until now have focused on the mechanisms controlling migration along the dorsolateral path. In comparison, our understanding of the mechanisms controlling NCC migration along the ventral path are complicated by the fact that this population comprises multiple precursors that form different derivatives in distinct regions of the embryo. For example, ventrally migrating NCCs either stop within the sclerotome in close association with the neural tube to form neurons and glia of the sensory nervous system (i.e. the dorsal root ganglia [DRG]), while other NCCs continue to migrate further ventrally to form the autonomic nervous system (i.e. sympathetic ganglia and chromaffin cells of the adrenal gland)

Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/

===Glossary===
----
===Reference list===

Talk:2018 Group Project 5

2018-10-03T12:32:14Z

Z5113627: /* Peer Reviews (Lab 10) */

{{2018ANAT2341ProjectHeader}}
{{2018ANAT2341ProjectDiscussion}}



[[User:Z5229399|Z5229399]] ([[User talk:Z5229399|talk]]) 11:33, 14 August 2018 (AEST)
[[User:Z5229597|Z5229597]] ([[User talk:Z5229597|talk]]) 11:34, 14 August 2018 (AEST)
[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 11:35, 14 August 2018 (AEST)
[[User:Z5229549|Z5229549]] ([[User talk:Z5229549|talk]]) 11:36, 14 August 2018 (AEST)
[[user:Z5229438|Z5229438]] ([[User talk:Z5229438|talk]]) 11:36, 21 August 2018 (AEST)

==Peer Reviews (Lab 10)==
[[User:Z5091101|Z5091101]] ([[User talk:Z5091101|talk]]) 20:14, 3 October 2018 (AEST)z5091101[[User:Z5091101|Z5091101]] ([[User talk:Z5091101|talk]]) 20:14, 3 October 2018 (AEST)
There has been an extensive use of references which is great especially since this topic seems to be really complex. Maybe a few more images for the beginning part of the article will make it look more user-friendly. Definitely have a look over for any grammar/spelling issues.

[[User:Z5164785|Z5164785]]Embryonic origins has been well-written. Proof-read for typing errors. Neural crest migration section shows good research and use of terminology. Neuronal and glial development has nice concise information though it might be wise to add some more content. Also if the heading will be Glial dev, then neuron dev should be changed to Neuronal dev- for consistency. Adult function of ? However, this section is well-written! Concise and relevant- great work guys! Tissue Structure is starting to look good however needs more content. Really good student drawn image!! Though it might be good to be the image higher up on the page.

Molecular mechanisms/factors/genes has overall been well written. Perhaps a brief statement about what transcription factors are?
Interesting image in abnormalities. I would personally appreciate an explanation of what I am seeing in the image. More discussion of a wider variety of abnormalities might be beneficial.
Excellent coverage of animals models so far!! May be one more? Also, great use of images!
Current research seems to be coming along well! Some formatting edits so that the video appears on the page would be good!

Overall, great work guys! Keep it up and move along with the project consistently!

[[User:Z5113627|Z5113627]]

History - empty, try and look for history of spinal nerve embryological discoveries as a potential starting point!

Embryonic Origins - good information, nice to read, but try and clean up the syntax just a little bit.

Developmental Process - Very clean and finished section with a thorough understanding of chemical mediators, overarching anatomy and embryological concepts.

Axonal Targeting - Try cleaning up the second sentence on Receptor Tyrosine Kinases, very good section otherwise.

Neuron Development - Good description of chemical mediators and their involvement in embryological processes

Glial Development - Also very good, as above. Consider adding a diagram or table, to simplify the knowledge into something your classmates can easily comprehend.

Adult Function - Could be mixed in with Tissue structure as one topic, otherwise both are good and set the stage of adult role & neurophysiology well.

Molecular Mechanisms - Fantastic all-round, not very much to fault, just try and preen up sentences here and there and proof-read, consider adding a little more information in a few sections, but only what would be necessary for the specific embryology.

Abnormalities, Animal Models and Current Research - All very well done, try simplifying some of the sentences occasionally.

References - Very good as well.

==Introduction==
*A good article for the overview of trunk neural crest cells

{{#pmid:28287247}}

[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 12:25, 24 August 2018 (AEST)

*Image about entire overview of neural crest migration

==History==

*find a image for the overview of DRG development
*if cannot find, use animal species to draw out the timeline
*work on chicken to identify origins of different components of DRG, neural crest
*timeline of discovery of DRG (use date of publication to put the timeline, around 1970s, original discovery is around 1930s)
*if cannot find about DRG, find about trunk neural crest

==Embryonic Origins==
*which particular part of the neural crest contribute to the DRG
*do they differentiate during migration or do they differentiate only when reaching the location
*which particular mechanism influence the differentiation process into DRG

==Developmental Process==
*extension of DRG to different end points (epithelium, joints, muscle fibres)
*good to include a timeline (schwann cells -> differentiation and myelination)
*understanding schwann cell differentiation and myelination
*neuronal cell death (apoptosis if they do not reach the cell type)

==Adult Function==
*Differentiation process
*When they start to function
==Tissue / Organ structure==
==Molecular Mechanisms / Factors / Genes==
*Tim

"Blocking of CXCR4 by morpholino or shRNA in premigratory chick trunk neural crest cells leads to significantly fewer cells that reach the dorsal aorta and instead populate the dorsal root ganglia"

{{#pmid:20881125}}

[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 12:18, 24 August 2018 (AEST)

*summary of signalling pathway and their interactions with each other
*identifying if molecular factors are growth or transcription factors

==Abnormalities / Abnormal development==
Dorsal Root Ganglionopathy is responsible for sensory impairment in CANVAS

“[[File:Dorsal Root Ganglion disorder.jpg]]”

"Sensory ganglionitis, variably called ganglionopathy, is a disease of sensory neurons in dorsal root ganglia. Major forms of these diseases are associated with neoplasm, Sjögren syndrome, and paraproteinemia or polyclonal gammopathy with or without known autoantibodies. Most cases follow subacute courses, but there are forms that develop chronically and acutely as well. Clinical signs seen include sensory ataxia exhibited by gait unsteadiness, a positive Romberg sign, reduced deep tendon reflexes, poor coordination, and pseudo-athetoid movements in the hands. Axonal degeneration warrants the treatment as early as possible. Early cases of immunologic origin that are immune-mediated may respond to plasmapheresis and immunosuppression. Differential diagnoses include environmental and industrial intoxication and adverse effects of antineoplastic and antibiotic drugs. The term “sensory neuronopathy” or “ganglionitis” refers to disorders of small neurons, larger neurons, and/or neurons of both sizes in the sensory ganglia."

==Animal Models==
"In zebrafish, trunk NCCs start migrating along a medial pathway in-between the somites and the NT. These NCCs align to and are affected by slow muscle cells in the middle part of the somite"

{{#pmid:16162652}}

[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 12:16, 24 August 2018 (AEST)

"Hedgehog (Hh) signal transduction is directly required in zebrafish DRG precursors for proper development of DRG neurons. Zebrafish mutations in the Hh signaling pathway result in the absence of DRG neurons and the loss of expression of neurogenin1 (ngn1), a gene required for determination of DRG precursors. Cell transplantation experiments demonstrate that Hh acts directly on DRG neuron precursors. Blocking Hh pathway activation at later stages of embryogenesis with the steroidal alkaloid, cyclopamine, further reveals that the requirement for a Hh signal response in DRG precursors correlates with the onset of ngn1 expression. These results suggest that Hh signaling may normally promote DRG development by regulating expression of ngn1 in DRG precursors."

Hedgehog signaling is directly required for the development of zebrafish dorsal root ganglia neurons. Josette M. Ungos, Rolf O. Karlstrom, David W. Raible. Development 2003 130: 5351-5362; doi: 10.1242/dev.00722

[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 00:25, 28 August 2018 (AEST)

[[File:Neural crest cell migration in erbb3b mutants.jpg]]

"Dorsal root ganglia (DRGs) arise from trunk neural crest cells that emerge from the dorsal neuroepithelium and coalesce into segmental streams that migrate ventrally along the developing somites. Proper formation of DRGs involves not only normal trunk neural crest migration, but also the ability of DRG progenitors to pause at a particular target location where they can receive DRG-promoting signals. In mammalian embryos, a receptor tyrosine kinase proto-oncogene, ErbB3, is required for proper trunk neural crest migration. Here, we show that in zebrafish mutants lacking ErbB3 function, neural crest cells do not pause at the location where DRGs normally form and DRG neurons are not generated. We also show that these mutants lack trunk neural crest-derived sympathetic neurons, but that cranial neural crest-derived enteric neurons appear normal. We isolated three genes encoding neuregulins, ErbB3 ligands, and show that two neuregulins function together in zebrafish trunk neural crest cell migration and in DRG formation. Together, our results suggest that ErbB3 signaling is required for normal migration of trunk, but not cranial, neural crest cells."

{{#pmid:18599505}}

[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 00:37, 28 August 2018 (AEST)

"cdon is expressed in developing premigratory NCCs but is downregulated once the cells become migratory. Knockdown of cdon results in aberrant migration of trunk NCCs: crestin positive cells can emigrate out of the neural tube but stall shortly after the initiation of migration. Live cell imaging analysis demonstrates reduced directedness of migration, increased velocity and mispositioned cell protrusions. In addition, transplantation analysis suggests that cdon is required cell-autonomously for directed NCC migration in the trunk."

{{#pmid:26256768}}

[[User:Z5229431|Z5229431]] ([[User talk:Z5229431|talk]]) 00:45, 28 August 2018 (AEST)

==Current research (Labs)==
--[[User:Z5229438|Z5229438]] ([[User talk:Z5229438|talk]]) 19:27, 27 August 2018 (AEST)
==Glossary==
*Brief, clear and concise
==Reference==

*HAVE A LIST OF ACRONYMS TO CONDENSE THE INFORMATION

User:Z5113627

2018-10-03T12:31:15Z

Z5113627: /* Dorsal Root Ganglia */

==Adrenal Gland and Neural Crest Cells==

{{Editing Links}}

==Reference List==

{{#pmid:30056110}}

In vitro maturation recent article {{#pmid:30056110|pmid:30056110}}

[[File:Neuropore cell shape changes.png|400px]]

Neuropore cell shape changes{{#pmid:30064364|PMID30064364}}

[[Help:Image Tutorial]]

<references/>

==Assessment - Peer Review==

===Melanocytes===

History of research is short, notes a few important researchers, lacks when melanocytes were connected to neural crest derivatives. It also lacks the knowledge of the role melanocytes play in human physiology and how that has changed, connection to Vitamin D synthesis and the history of the role melanocytes play in pathology could also be added.

Tissue Organ Structure and Function -
Skin is completely missing, no images or text to be seen.
Ear is well explained both in writing and images, understanding of chemical mediation in the adult has been elucidated, no reference to physiological role of the ear and how it achieves it, it would not have to be long. Figure 2 refers to Wv/Wv mutant, what is a Wv/Wv mutant? There is no explanation of this mutant model, whether it is in humans or animals, or why it is important etc.
Eyes section notes the combined role of neural-crest derived cells and neuroepithelium of optic cup, explains the layers of the eye nicely within the associated image of Figure 4, which has been correctly formatted and cited.
The heart section simply shows an image of a cardiac melanocyte, there should be more here.
The CNS topic is short, but it does note the understanding of a role of melanocytes in CNS, but nothing more about how neural crest cells help with giving melanocytes to the CNS, the image is a nice overview of the skull and layers of the scalp.

Embryonic origins, Developmental time course and Molecular Mechanisms / Factors / Genes are all blank, with no images to be seen.

Reference to a mouse model can be seen in the Animal models section, are there other models in other species of mouse mutant that can observe melanocyte embryology? Mention of the melanoma model of genetically-engineered mice is good, but how does it relate to neural crest abnormality?

Current Research explains 2 new systems to observe melanocytes, this section could show findings and how they're important - could be longer. Abnormalities listed are short, some missing entirely, more focus on which are more common could be noted due to the vast nature of melanocytes. Glossary is nice but incomplete, and there are a sufficient number of references.

===Cardiac===

Introduction - Short but does nicely explain some of the important aspects of cardiogenesis, the sentences could be ordered more cleanly and could allude to more than just animal models and their connection to neural crest and DiGeorge Syndrome in humans. History of knowledge of cardiogenesis maybe?

Development of the Cardiovascular System - Could possibly be retitled? (There is no mention of peripheral vasculature that is a part of the cardiovascular system, you have simply referred to cardiogenesis: the formation of the heart). The developmental timecourse is good at explaining the important events in cardiogenesis and what weeks they correspond to. The embedded video is also good, but is quite long at 9 minutes.

Cardiac Neural Crest Cells - This is a good introduction to the specific neural crest population that contribute to cardiogenesis. However, there are a few issues with sentence formatting, grammar and referencing that could be cleaned up. The mention of neural crest's pluropotentiality is perfect in understanding how the different tissue types of the valvular structures arise, so that is definitely a strong point of the section.

Early Development - Very good, key chemical mediators are mentioned, could more be explained about what they are and how they relate to neural crest specifically? An explanation on the circumpharyngeal ridge would also be welcomed.

Later Development - Very nice partitioning diagram, Valvulogenesis section could be longer, it is very important. The same can be said for Atrial and Ventricular Separation.

Signalling Molecules - Good overview, more links to literature would be appreciated than just Meis-2, more could be added if necessary to discussion.

Developmental Time Course appears incomplete, this needs to be more specific.

Abnormalities - Seem quite well discussed, formatting needs some work as well as general cleaning with references, diagrams of a histology section or relevant macroscopic specimen would be welcome here to understand the pathology and how it relates to the embryology.

Research - Same as above, but there seems to be less information as well: there needs to be more content, directed referencing, images if necessary, and specific examples of mutant, knock-out or other genetically-engineered models to observe these embryological findings. There is good mention of the different animal models that are used to observe cardiogenesis (mouse, fish and chicken) but otherwise, it needs some work.

Glossary and References - Very few current references at the bottom, I assume this is because the bulk of them have not been formatted correctly, most appear to be from research literature and medical science journals, no current glossary might be an issue if there are many acronyms.

===Dorsal Root Ganglia===

History - empty, try and look for history of spinal nerve embryological discoveries as a potential starting point!

Embryonic Origins - good information, nice to read, but try and clean up the syntax just a little bit.

Developmental Process - Very clean and finished section with a thorough understanding of chemical mediators, overarching anatomy and embryological concepts.

Axonal Targeting - Try cleaning up the second sentence on Receptor Tyrosine Kinases, very good section otherwise.

Neuron Development - Good description of chemical mediators and their involvement in embryological processes

Glial Development - Also very good, as above. Consider adding a diagram or table, to simplify the knowledge into something your classmates can easily comprehend.

Adult Function - Could be mixed in with Tissue structure as one topic, otherwise both are good and set the stage of adult role & neurophysiology well.

Molecular Mechanisms - Fantastic all-round, not very much to fault, just try and preen up sentences here and there and proof-read, consider adding a little more information in a few sections, but only what would be necessary for the specific embryology.

Abnormalities, Animal Models and Current Research - All very well done, try simplifying some of the sentences occasionally.

References - Very good as well.

User:Z5113627

2018-10-02T09:10:44Z

Z5113627: /* Assessment */

User:Z5113627

2018-10-02T09:10:01Z

Z5113627: /* Cardiac */

==Adrenal Gland and Neural Crest Cells==

{{Editing Links}}

==Reference List==

{{#pmid:30056110}}

In vitro maturation recent article {{#pmid:30056110|pmid:30056110}}

[[File:Neuropore cell shape changes.png|400px]]

Neuropore cell shape changes{{#pmid:30064364|PMID30064364}}

[[Help:Image Tutorial]]

<references/>

==Assessment==

===Melanocytes===

History of research is short, notes a few important researchers, lacks when melanocytes were connected to neural crest derivatives. It also lacks the knowledge of the role melanocytes play in human physiology and how that has changed, connection to Vitamin D synthesis and the history of the role melanocytes play in pathology could also be added.

Tissue Organ Structure and Function -
Skin is completely missing, no images or text to be seen.
Ear is well explained both in writing and images, understanding of chemical mediation in the adult has been elucidated, no reference to physiological role of the ear and how it achieves it, it would not have to be long. Figure 2 refers to Wv/Wv mutant, what is a Wv/Wv mutant? There is no explanation of this mutant model, whether it is in humans or animals, or why it is important etc.
Eyes section notes the combined role of neural-crest derived cells and neuroepithelium of optic cup, explains the layers of the eye nicely within the associated image of Figure 4, which has been correctly formatted and cited.
The heart section simply shows an image of a cardiac melanocyte, there should be more here.
The CNS topic is short, but it does note the understanding of a role of melanocytes in CNS, but nothing more about how neural crest cells help with giving melanocytes to the CNS, the image is a nice overview of the skull and layers of the scalp.

Embryonic origins, Developmental time course and Molecular Mechanisms / Factors / Genes are all blank, with no images to be seen.

Reference to a mouse model can be seen in the Animal models section, are there other models in other species of mouse mutant that can observe melanocyte embryology? Mention of the melanoma model of genetically-engineered mice is good, but how does it relate to neural crest abnormality?

Current Research explains 2 new systems to observe melanocytes, this section could show findings and how they're important - could be longer. Abnormalities listed are short, some missing entirely, more focus on which are more common could be noted due to the vast nature of melanocytes. Glossary is nice but incomplete, and there are a sufficient number of references.

===Cardiac===

Introduction - Short but does nicely explain some of the important aspects of cardiogenesis, the sentences could be ordered more cleanly and could allude to more than just animal models and their connection to neural crest and DiGeorge Syndrome in humans. History of knowledge of cardiogenesis maybe?

Development of the Cardiovascular System - Could possibly be retitled? (There is no mention of peripheral vasculature that is a part of the cardiovascular system, you have simply referred to cardiogenesis: the formation of the heart). The developmental timecourse is good at explaining the important events in cardiogenesis and what weeks they correspond to. The embedded video is also good, but is quite long at 9 minutes.

Cardiac Neural Crest Cells - This is a good introduction to the specific neural crest population that contribute to cardiogenesis. However, there are a few issues with sentence formatting, grammar and referencing that could be cleaned up. The mention of neural crest's pluropotentiality is perfect in understanding how the different tissue types of the valvular structures arise, so that is definitely a strong point of the section.

Early Development - Very good, key chemical mediators are mentioned, could more be explained about what they are and how they relate to neural crest specifically? An explanation on the circumpharyngeal ridge would also be welcomed.

Later Development - Very nice partitioning diagram, Valvulogenesis section could be longer, it is very important. The same can be said for Atrial and Ventricular Separation.

Signalling Molecules - Good overview, more links to literature would be appreciated than just Meis-2, more could be added if necessary to discussion.

Developmental Time Course appears incomplete, this needs to be more specific.

Abnormalities - Seem quite well discussed, formatting needs some work as well as general cleaning with references, diagrams of a histology section or relevant macroscopic specimen would be welcome here to understand the pathology and how it relates to the embryology.

Research - Same as above, but there seems to be less information as well: there needs to be more content, directed referencing, images if necessary, and specific examples of mutant, knock-out or other genetically-engineered models to observe these embryological findings. There is good mention of the different animal models that are used to observe cardiogenesis (mouse, fish and chicken) but otherwise, it needs some work.

Glossary and References - Very few current references at the bottom, I assume this is because the bulk of them have not been formatted correctly, most appear to be from research literature and medical science journals, no current glossary might be an issue if there are many acronyms.

Talk:2018 Group Project 4

2018-10-02T09:09:14Z

Z5113627: /* Peer Reviews (Lab 10) */

{{2018ANAT2341ProjectHeader}}
= Neural Crest and Cardiovascular Development =
{{2018ANAT2341ProjectDiscussion}}



==Peer Reviews (Lab 10)==
[[User:Z5164785|Z5164785]] Some editing required for the formatting (introduction, development of the cardiovascular system etc)
Good use of the video- excellent aid for later understanding of what you guys discuss!

Great research exhibited in the cardiac neural crest cells section; an image to go beside it would be great. References need to be formatted correctly so that they are’t displayed in the written information.

I like how early development has been broken down. However, how come they’re numbered here but not in later development? Clear and concise information presented in induction. In the neural crest to circumpharangeal ridge section, perhaps bold/underline the signalling factors so it’s clear. The formation of pharyngeal arches … section also has good information! An image for this section especially would be beneficial.

As a whole, the later development section is also good. Mostly clear and concise information.  Some proof-reading would be good.

Some more information about the signaling molecules would be good- perhaps tie to back to what was mentioned in the circumpharangeal section?

The time course is also good! I like the selection of heart diseases and how they’ve been discussed. Perhaps some additional information about symptoms, epidemiology etc would be good but that’s just a suggestion.

Overall, great work guys! Keep it up and move along with the project consistently! Perhaps include some student-drawn images. I like the planning- if you keep at it you’ll have an awesome project!

[[User:Z5229189|Z5229189]] ([[User talk:Z5229189|talk]]) 12:28, 14 August 2018 (AEST)

Points to take note:
- Need to describe in content how neural crest links to development of heart, rather than just talking about development of heart
- Acronyms used to be listed at end of page
- Correct Referencing

[[User:Z5113627|Z5113627]]

Introduction - Short but does nicely explain some of the important aspects of cardiogenesis, the sentences could be ordered more cleanly and could allude to more than just animal models and their connection to neural crest and DiGeorge Syndrome in humans. History of knowledge of cardiogenesis maybe?

Development of the Cardiovascular System - Could possibly be retitled? (There is no mention of peripheral vasculature that is a part of the cardiovascular system, you have simply referred to cardiogenesis: the formation of the heart). The developmental timecourse is good at explaining the important events in cardiogenesis and what weeks they correspond to. The embedded video is also good, but is quite long at 9 minutes.

Cardiac Neural Crest Cells - This is a good introduction to the specific neural crest population that contribute to cardiogenesis. However, there are a few issues with sentence formatting, grammar and referencing that could be cleaned up. The mention of neural crest's pluropotentiality is perfect in understanding how the different tissue types of the valvular structures arise, so that is definitely a strong point of the section.

Early Development - Very good, key chemical mediators are mentioned, could more be explained about what they are and how they relate to neural crest specifically? An explanation on the circumpharyngeal ridge would also be welcomed.

Later Development - Very nice partitioning diagram, Valvulogenesis section could be longer, it is very important. The same can be said for Atrial and Ventricular Separation.

Signalling Molecules - Good overview, more links to literature would be appreciated than just Meis-2, more could be added if necessary to discussion.

Developmental Time Course appears incomplete, this needs to be more specific.

Abnormalities - Seem quite well discussed, formatting needs some work as well as general cleaning with references, diagrams of a histology section or relevant macroscopic specimen would be welcome here to understand the pathology and how it relates to the embryology.

Research - Same as above, but there seems to be less information as well: there needs to be more content, directed referencing, images if necessary, and specific examples of mutant, knock-out or other genetically-engineered models to observe these embryological findings. There is good mention of the different animal models that are used to observe cardiogenesis (mouse, fish and chicken) but otherwise, it needs some work.

Glossary and References - Very few current references at the bottom, I assume this is because the bulk of them have not been formatted correctly, most appear to be from research literature and medical science journals, no current glossary might be an issue if there are many acronyms.

=Neural Crest and Cardiac Development=

===Introduction/histology/anatomy/physiology===

===History of cardiac neural crest cells===

https://www.ncbi.nlm.nih.gov/pubmed/17429214

https://www.ncbi.nlm.nih.gov/pubmed/29158447

===Structure of the Heart===
The heart is a muscular organ which plays a critical role in the circulatory system by mechinically pumping blood to various organs around the body for the exchange of nutrients and gases. It is located..... The heart has four different chambers which are compartmentalized by semilunar and atrioventricular valves into the left and right atria and ventricles
[[User:Z5229185|Z5229185]] ([[User talk:Z5229185|talk]]) 11:43, 4 September 2018 (AEST)

"During early development, neural folds are formed along the anteroposterior-axis in the ectoderm. Upon fusion, the folds give rise to the neural tube. During the process of neural tube formation, cells detach at the border of the neural and epidermal ectoderm, i.e. at the dorsal aspect of the forming neural tube. These cells are referred to as neural crest cells. Neural crest cells migrate along defined pathways throughout the body. Upon arrival at their destination, they differentiate into various cell types, among which melanocytes, peripheral neurons and their supporting cells, and skeletal elements. The neural crest cells are formed along the entire cranio-caudal axis of the body and can be divided into two major populations the cranial and truncal neural crest cells. The cranial neural crest extends from the diencephalon up to somite pair 5, and the truncal neural crest from somite pair 6 to the caudal end of the neural tube. The truncal neural crest is involved in sympathetic innervation of the heart, whereas the cranial neural crest is associated with parasympathetic innervation of the heart."

{{#pmid:10946058}}

[[User:Z5229185|Z5229185]] ([[User talk:Z5229185|talk]]) 11:51, 21 August 2018 (AEST) Sounds good for a brief introduction of the neural crest roles to the heart development

"The subpopulation of neural crest cells responsible for aorticopulmonary septation has been termed the cardiac neural crest. CNCCs are required for the normal development of the thymus, thyroid, parathyroids, cardiac conduction system, semilunar valves, parasympathetic innervation of the heart, and outflow septum, as well as proper remodeling of the pharyngeal arch arteries and alignment of the outflow with the ventricles. "

{{#pmid:25227322}}

[[User:Z5229185|Z5229185]] ([[User talk:Z5229185|talk]]) 07:40, 23 August 2018 (AEST)

This page will give a brief understanding of the cardiac anatomy and how the organ develops. To give the reader a basis of how the neural crest forms the heart n and all of its valves and what happens when mechanisms (abnormal migration patterns) of the neural crest cause malfunctions and generate deformities in the growing embryo.

===Embryonic origins/embyronic contributions===
https://onlinelibrary.wiley.com/doi/full/10.1002/bdrc.21081
This article is great for the origins/process of the neural create, basic information in terms readable by most and will be a basis fro understanding the neural crest.

The neural crest is the name given to the strip of cells at the junction between neural and epidermal ectoderm in neurula‐stage vertebrate embryos, which is later brought to the dorsal neural tube as the neural folds elevate. The neural crest is a heterogeneous and multipotent progenitor cell population whose cells undergo EMT then extensively and accurately migrate throughout the embryo. Neural crest cells contribute to nearly every organ system in the body, with derivatives of neuronal, glial, neuroendocrine, pigment, and also mesodermal lineages. This breadth of developmental capacity has led to the neural crest being termed the fourth germ layer.

https://onlinelibrary.wiley.com/doi/full/10.1002/bdrc.21081#citedby-section

numerous authors collaborated on the information above.

===Early development===
"Cardiac neural crest cells originate from the neural tube extending from the axial level of the mid otic placode to the third somite in chick. The cells then migrate from the neural tube into the caudal pharyngeal arches (3, 4 and 6). Some neural crest cells remain in the pharynx to support aortic arch artery development, while a subpopulation continues on to migrate into the outflow tract of the heart"

{{#pmid:22595346}}

[[User:Z5229185|Z5229185]] ([[User talk:Z5229185|talk]]) 09:22, 28 August 2018 (AEST)

[[File:Progressive development of the Embryonic Heart.jpeg|750px]]
[[User:Z5229185|Z5229185]] ([[User talk:Z5229185|talk]]) 11:13, 24 August 2018 (AEST)

[[File:Cardiacdevelopment1.jpg]]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2375817/
[[User:Z5229177|Z5229177]] ([[User talk:Z5229177|talk]]) 09:07, 28 August 2018 (AEST)

===Later development===
===Developmental time course/carnegie stages/overview===
===Cell signalling involved/molecular mechanisms/factors/genes===
https://discovery.lifemapsc.com/library/images/neural-crest-development
photo I want to use for the project

[[File:Migrating Neural Crest cells.png]]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113226/

Article talking about hormones regulating the migration of neural crest cells to different destinations of the body.

===Disorders/abnormalities===
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3389200/ Article explains congenital defects of the heart from the neural crest and how the defects happen at the molecular level

"Cardiac neural crest ablation experiments demonstrated that upon removal of the pre-migratory cardiac neural crest cardiovascular abnormalities are induced. The pre-migratory neural crest is ablated by removal of the dorsal aspects of the neural folds using vibrating needles, tungsten needles, or laser. Entire removal of the cardiac neural crest showed in almost all cases a persistent truncus arteriosus (PTA). However, the chicken neural crest ablation phenotype also includes abnormal patterning of the great arteries that are derived from the aortic arches, absence or hypoplastic thymus, thyroid and parathyroids. As expected, removal of only the cardiac neural crest does not effect the innervation of the heart and does not lead to craniofacial abnormalities. Interestingly, partial ablation of the cardiac neural crest results in a milder cardiac phenotype, like double outlet right ventricle, dextraposed aorta, tetralogy of Fallot, and/or ventricle septum defect, whereas the other phenotypic alterations are hardly different from complete cardiac neural crest ablation [17,26–29]. Based on these ablation studies it was concluded that PTA only occurred when the numbers of neural crest cells were reduced below a critical level that is no longer compatible with proper formation of the aortico-pulmonary septum [5,30]. Thus, the ablation experiments are in agreement with the conclusion of Conway and coworkers [1] suggesting that the quantity rather than the quality of neural crest cells is important in OFT septation."

{{#pmid:10946058}}

[[User:Z5229185|Z5229185]] ([[User talk:Z5229185|talk]]) 11:58, 21 August 2018 (AEST)

=== Brief overview of Heart Development===
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC408374/ Explains heart development, great for basic understanding and good for continuing research about the heart.

===Current research/main animal models/future questions===

==Reference==
PMID: 10359559
{{#pmid:10359559}}

<pubmed limit=5>Neural Crest Embryology</pubmed>

A novel role for cardiac neural crest in heart development

PMID: 10359559
{{#pmid:10359559}}

=Google doc=

Discussed between all group members on google docs.

Neural crest and cardiovascular development/cardiac neural crest
OUTFLOW TRACT
VALVE

Group project 2017 on heart development: https://embryology.med.unsw.edu.au/embryology/index.php/2017_Group_Project_3

The key points relating to the topic that your group allocated are clearly described.
The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.
Content is correctly cited and referenced.
The wiki has an element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations.
Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.
Relates the topic and content of the Wiki entry to learning aims of embryology.
Clearly reflects on editing/feedback from group peers and articulates how the Wiki could be improved (or not) based on peer comments/feedback. Demonstrates an ability to review own work when criticised in an open edited wiki format. Reflects on what was learned from the process of editing a peer's wiki.
Evaluates own performance and that of group peers to give a rounded summary of this wiki process in terms of group effort and achievement.
The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic and covered the key areas necessary to inform your peers in their learning.
Develops and edits the wiki entries in accordance with the above guidelines.

What should be on the page:
Table of contents
Introduction
History
Embryonic origins/embryonic contributions
Carnegie stages
Early development
Later development
Structure of the cardiovascular network
Developmental time course
Developmental/adult function
Tissue/organ structure / histology
Cell signalling involved/Molecular mechanisms/factors/genes
Anatomy of the cardiov
Functions of the cardiov
Abnormalities associated with the development of the cardiov
Models and Research (past/current/future)
Disorders: DiGeorge syndrome
Main animal model system
Current research (labs)
Future questions
Glossary (for all the acronyms)
Reference list

SO:
introduction/history/structure of the cardiovascular network/histology/anatomy/physiology
Embryonic origins/embyronic contributions
Early development
Later development
Developmental time course/carnegie stages/overview
Cell signalling involved/molecular mechanisms/factors/genes
Disorders/abnormalities:
Current research/main animal models/future questions

how to write a good project:
content
its brevity and balance between text and images: dont make it pages & pages on text ,it is a webpage!! balance the content. Keep your editing tight. Don’t make your whole project bulletpoints.
Like to see some drawings done by ourselves

Good articles on neural crest & cardiovascular development:

https://search.proquest.com/docview/222534802?pq-origsite=gscholar

https://www.ncbi.nlm.nih.gov/pubmed/25662261 (REVIEW article)

https://embryology.med.unsw.edu.au/embryology/index.php/Lecture_-_Neural_Crest_Development → Neural crest lecture

https://www.sciencedirect.com/science/article/pii/S0301468112000667?via%3Dihub (Review article by AnnaKeyte, Mary Redmond)
-> The neural crest in cardiac congenital anomalies/ a little on history

https://www.ncbi.nlm.nih.gov/books/NBK10065/ Article gives a good synopsis of nerual crest cardiac development.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC408374/ Article has a lot of information about heart development from the nerual crest, great article to start out with for beginning infromation.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3389200/
Congential defects of the heart during development and abnormalities, article with substantial information about what happens to the heart when the nerual crest is defected.

https://www.heartrhythmjournal.com/article/S1547-5271(06)02148-5/fulltext Great review article that has a lot of references to other scholarly papers we can use for a better understanding and more in depth information about cardiac valves.

https://www.ahajournals.org/doi/abs/10.1161/01.res.0000259041.37059.8c Essential protein needed for cardiac development.

https://www.ncbi.nlm.nih.gov/pubmed/25227568
This article gives a great description of the neural crest and the history of the neural crest and good information that is basic and informative. Will allow us to get the introduction of our webpage started and will be a branching point to move forward.

1: Introduction/history/structure of the cardiovascular network/histology/anatomy/physiology
→ Also explain what neural crest cells are?

History: (In a chick study of parasympathetic innervation of the heart, Margaret Kirby and colleagues ablated neural crest and serendi
pitously discovered that the embryos lacked aorticopulmonary septation (Kirby et al., 1983). The subregion of cranial neural crest ablated by Dr. Kirby has been called the “cardiac neural crest”, not because the cells of this region migrate solely to the heart, but for the importance of crest-derived ectomesenchyme in cardiovascular development.) -> Article by Anna Keyte

2: Embryonic origins/embryonic contributions

Neural crest at the level of the body have two general migration pathways, defined by the position of the somite:
medial pathway: between the neural tube and the somite
Lateral pathway: between the somite and the body wall (cardiac NCC)

Outflow tract
Valves

Cardiac neural crest cells (CNCCs) are a type of neural crest cells that migrate to the circumpharyngeal ridge (an arc-shape ridge above the pharyngeal arches) and then into the 3rd, 4th and 6th pharyngeal arches and the cardiac outflow tract. They extend from the otic placodes (the structure in developing embryos that will later form the ears) to the third somites (clusters of mesoderm that will become skeletal muscle, vertebrae and dermis). The cardiac neural crest cells have a number of functions including creation of the muscle and connective tissue walls of large arteries, parts of the cardiac septum, parts of the thyroid, parathyroid and thymus glands. They differentiate into melanocytes and neurons and the cartilage and connective tissue of the pharyngeal arches. They may also contribute to the creation of the carotid body, the organ which monitors oxygen in the lood and regulates breathing.

--- BEFORE THE CARDIAC NEURAL CREST CELL --

3: Early development

In higher vertebrates:
Cells in the cranial neural crest migrate in clusters or “streams” and later form cranial nerve ganglia at even-numbered rhombomeres proximally.
Specifically, the cranial crest migrates in three streams referred to as first or cranial, second or middle and third or caudal. The caudal stream comprises most of the cardiac crest. The majority of the crest emanate from the even numbered rhombomeres.

4: Later development

5: Developmental time course/carnegie stages/overview

6: Cell signalling involved/molecular mechanisms/factors/genes

Neural Crest Cells (NCCs) is essential in earlier stages of arterial valve development such as positioning the cushions and patterning valve leaflets (patterning)

7: Disorders/abnormalities

Abnormalities of arterial valves (Bicuspid aortic valve BAV)
DiGeorge syndrome

-Failure of outflow septation is a hallmark of cardiac neural crest ablation and is called persistent truncus arteriosus (PTA) (6–8). The common outflow vessel usually arises from the right ventricle and is always accompanied by abnormal patterning of the great arteries (9, 10).The most severe alteration in ventricular function is decreased ejection fraction. In addition to changes in ventricular function, abnormal morphology of the heart loop in early neural crest–ablated embryos has been reported (7, 13–16). All of these data indicate that cardiac neural crest ablation affects early heart development.

8: Current research/main animal models/future questions

Focus on overview of how the heart develops don't go too much in depth or else the project becomes a cardiac development page and that is not what the project is about. Go in depth to how the neural crest leads to abnormalities of the heart and what the neural crest does. Be brief about the heart development to give the reader a basic understanding about the heart then in depth discussion and development about the neural crest.\

[[User:Z5229281|Z5229281]] ([[User talk:Z5229281|talk]]) 12:47, 14 August 2018 (AEST)

[[User:Z5229185|Z5229185]] ([[User talk:Z5229185|talk]]) 12:48, 14 August 2018 (AEST)

[[User:Z5229177|Z5229177]] ([[User talk:Z5229177|talk]]) 12:49, 14 August 2018 (AEST)

[[User:Z5229189|Z5229189]] ([[User talk:Z5229189|talk]]) 12:51, 14 August 2018 (AEST)
[[User:Z5229281|Z5229281]] ([[User talk:Z5229281|talk]]) 12:05, 21 August 2018 (AEST)z5229281[[User:Z5229281|Z5229281]] ([[User talk:Z5229281|talk]]) 12:05, 21 August 2018 (AEST)

Talk:2018 Group Project 3

2018-10-02T09:07:22Z

Z5113627: /* Assessment */

{{2018ANAT2341ProjectHeader}}
{{2018ANAT2341ProjectDiscussion}}


[[User:Z5229549|Z5229549]] ([[User talk:Z5229549|talk]]) 12:20, 14 August 2018 (AEST)
hi

[[User:Z5165679|Z5165679]] ([[User talk:Z5165679|talk]]) 12:20, 14 August 2018 (AEST)

[[User:Z5164785|Z5164785]] ([[User talk:Z5164785|talk]]) 12:20, 14 August 2018 (AEST)

[[User:Z5229132|Z5229132]] ([[User talk:Z5229132|talk]]) 12:21, 14 August 2018 (AEST)

Melanocytes

Development from neural crest

Areas found:
eyes
ears
heart
central nervous system meninges

Problems:
Hearing
Melanoma
vision

Intro

History

Embryonic origins

development time course

developmental/adult function

tissue/organ structure

molecular mechanisms/factors/genes

abnormalities/abnormal development

animal models

current research

glossary - useful when you have lots of acronyms. Be brief and clear
ref. list - generates itself as long as you ref. properly

needs to be explained to another uni student that doesn’t know anything about neural crest and its differentiation.

Key things to understand on what makes a good project page:
-Content
-Brevity and balance between text and images - it’s an online resource, not a textbook. BALANCE CONTENT.
-can have numbered lists and bullet points but don’t turn whole project into this.

If you can’t publish an image directly, you can redraw it and credit it to the article.

- differentiation
ho they get to different parts of the body
where the local singals come from etc
pigmentation and vitamin D

animal models

[[User:Z5229321|Z5229132]] ([[User talk:Z5229132|talk]]) 16:04, 04 September 2018 (AEST)
everyone on intro
z5229132 - history
z5165679 - animal models and current research
z5229549 - embryonic origins

=Assessment - Peer Review=

===Melanocytes===
[[User:Z5113627|Z5113627]]

History of research is short, notes a few important researchers, lacks when melanocytes were connected to neural crest derivatives. It also lacks the knowledge of the role melanocytes play in human physiology and how that has changed, connection to Vitamin D synthesis and the history of the role melanocytes play in pathology could also be added.

Tissue Organ Structure and Function -
Skin is completely missing, no images or text to be seen.
Ear is well explained both in writing and images, understanding of chemical mediation in the adult has been elucidated, no reference to physiological role of the ear and how it achieves it, it would not have to be long. Figure 2 refers to Wv/Wv mutant, what is a Wv/Wv mutant? There is no explanation of this mutant model, whether it is in humans or animals, or why it is important etc.
Eyes section notes the combined role of neural-crest derived cells and neuroepithelium of optic cup, explains the layers of the eye nicely within the associated image of Figure 4, which has been correctly formatted and cited.
The heart section simply shows an image of a cardiac melanocyte, there should be more here.
The CNS topic is short, but it does note the understanding of a role of melanocytes in CNS, but nothing more about how neural crest cells help with giving melanocytes to the CNS, the image is a nice overview of the skull and layers of the scalp.

Embryonic origins, Developmental time course and Molecular Mechanisms / Factors / Genes are all blank, with no images to be seen.

Reference to a mouse model can be seen in the Animal models section, are there other models in other species of mouse mutant that can observe melanocyte embryology? Mention of the melanoma model of genetically-engineered mice is good, but how does it relate to neural crest abnormality?

Current Research explains 2 new systems to observe melanocytes, this section could show findings and how they're important - could be longer. Abnormalities listed are short, some missing entirely, more focus on which are more common could be longer. Abnormalities listed are short, some missing entirely, more focus on which are more common could be noted due to the vast nature of melanocytes. Glossary is nice but incomplete, and there are a sufficient number of references.

Talk:2018 Group Project 3

2018-10-02T09:06:50Z

Z5113627: /* Assessment */

{{2018ANAT2341ProjectHeader}}
{{2018ANAT2341ProjectDiscussion}}


[[User:Z5229549|Z5229549]] ([[User talk:Z5229549|talk]]) 12:20, 14 August 2018 (AEST)
hi

[[User:Z5165679|Z5165679]] ([[User talk:Z5165679|talk]]) 12:20, 14 August 2018 (AEST)

[[User:Z5164785|Z5164785]] ([[User talk:Z5164785|talk]]) 12:20, 14 August 2018 (AEST)

[[User:Z5229132|Z5229132]] ([[User talk:Z5229132|talk]]) 12:21, 14 August 2018 (AEST)

Melanocytes

Development from neural crest

Areas found:
eyes
ears
heart
central nervous system meninges

Problems:
Hearing
Melanoma
vision

Intro

History

Embryonic origins

development time course

developmental/adult function

tissue/organ structure

molecular mechanisms/factors/genes

abnormalities/abnormal development

animal models

current research

glossary - useful when you have lots of acronyms. Be brief and clear
ref. list - generates itself as long as you ref. properly

needs to be explained to another uni student that doesn’t know anything about neural crest and its differentiation.

Key things to understand on what makes a good project page:
-Content
-Brevity and balance between text and images - it’s an online resource, not a textbook. BALANCE CONTENT.
-can have numbered lists and bullet points but don’t turn whole project into this.

If you can’t publish an image directly, you can redraw it and credit it to the article.

- differentiation
ho they get to different parts of the body
where the local singals come from etc
pigmentation and vitamin D

animal models

[[User:Z5229321|Z5229132]] ([[User talk:Z5229132|talk]]) 16:04, 04 September 2018 (AEST)
everyone on intro
z5229132 - history
z5165679 - animal models and current research
z5229549 - embryonic origins

=Assessment=

===Melanocytes===
[[User:Z5113627|Z5113627]]

History of research is short, notes a few important researchers, lacks when melanocytes were connected to neural crest derivatives. It also lacks the knowledge of the role melanocytes play in human physiology and how that has changed, connection to Vitamin D synthesis and the history of the role melanocytes play in pathology could also be added.

Tissue Organ Structure and Function -
Skin is completely missing, no images or text to be seen.
Ear is well explained both in writing and images, understanding of chemical mediation in the adult has been elucidated, no reference to physiological role of the ear and how it achieves it, it would not have to be long. Figure 2 refers to Wv/Wv mutant, what is a Wv/Wv mutant? There is no explanation of this mutant model, whether it is in humans or animals, or why it is important etc.
Eyes section notes the combined role of neural-crest derived cells and neuroepithelium of optic cup, explains the layers of the eye nicely within the associated image of Figure 4, which has been correctly formatted and cited.
The heart section simply shows an image of a cardiac melanocyte, there should be more here.
The CNS topic is short, but it does note the understanding of a role of melanocytes in CNS, but nothing more about how neural crest cells help with giving melanocytes to the CNS, the image is a nice overview of the skull and layers of the scalp.

Embryonic origins, Developmental time course and Molecular Mechanisms / Factors / Genes are all blank, with no images to be seen.

Reference to a mouse model can be seen in the Animal models section, are there other models in other species of mouse mutant that can observe melanocyte embryology? Mention of the melanoma model of genetically-engineered mice is good, but how does it relate to neural crest abnormality?

Current Research explains 2 new systems to observe melanocytes, this section could show findings and how they're important - could be longer. Abnormalities listed are short, some missing entirely, more focus on which are more common could be longer. Abnormalities listed are short, some missing entirely, more focus on which are more common could be noted due to the vast nature of melanocytes. Glossary is nice but incomplete, and there are a sufficient number of references.

Talk:2018 Group Project 3

2018-10-02T09:06:18Z

Z5113627: /* Melanocytes */

{{2018ANAT2341ProjectHeader}}
{{2018ANAT2341ProjectDiscussion}}


[[User:Z5229549|Z5229549]] ([[User talk:Z5229549|talk]]) 12:20, 14 August 2018 (AEST)
hi

[[User:Z5165679|Z5165679]] ([[User talk:Z5165679|talk]]) 12:20, 14 August 2018 (AEST)

[[User:Z5164785|Z5164785]] ([[User talk:Z5164785|talk]]) 12:20, 14 August 2018 (AEST)

[[User:Z5229132|Z5229132]] ([[User talk:Z5229132|talk]]) 12:21, 14 August 2018 (AEST)

Melanocytes

Development from neural crest

Areas found:
eyes
ears
heart
central nervous system meninges

Problems:
Hearing
Melanoma
vision

Intro

History

Embryonic origins

development time course

developmental/adult function

tissue/organ structure

molecular mechanisms/factors/genes

abnormalities/abnormal development

animal models

current research

glossary - useful when you have lots of acronyms. Be brief and clear
ref. list - generates itself as long as you ref. properly

needs to be explained to another uni student that doesn’t know anything about neural crest and its differentiation.

Key things to understand on what makes a good project page:
-Content
-Brevity and balance between text and images - it’s an online resource, not a textbook. BALANCE CONTENT.
-can have numbered lists and bullet points but don’t turn whole project into this.

If you can’t publish an image directly, you can redraw it and credit it to the article.

- differentiation
ho they get to different parts of the body
where the local singals come from etc
pigmentation and vitamin D

animal models

[[User:Z5229321|Z5229132]] ([[User talk:Z5229132|talk]]) 16:04, 04 September 2018 (AEST)
everyone on intro
z5229132 - history
z5165679 - animal models and current research
z5229549 - embryonic origins

=Assessment=

===Melanocytes=== [[User:Z5113627|Z5113627]]

History of research is short, notes a few important researchers, lacks when melanocytes were connected to neural crest derivatives. It also lacks the knowledge of the role melanocytes play in human physiology and how that has changed, connection to Vitamin D synthesis and the history of the role melanocytes play in pathology could also be added.

Tissue Organ Structure and Function -
Skin is completely missing, no images or text to be seen.
Ear is well explained both in writing and images, understanding of chemical mediation in the adult has been elucidated, no reference to physiological role of the ear and how it achieves it, it would not have to be long. Figure 2 refers to Wv/Wv mutant, what is a Wv/Wv mutant? There is no explanation of this mutant model, whether it is in humans or animals, or why it is important etc.
Eyes section notes the combined role of neural-crest derived cells and neuroepithelium of optic cup, explains the layers of the eye nicely within the associated image of Figure 4, which has been correctly formatted and cited.
The heart section simply shows an image of a cardiac melanocyte, there should be more here.
The CNS topic is short, but it does note the understanding of a role of melanocytes in CNS, but nothing more about how neural crest cells help with giving melanocytes to the CNS, the image is a nice overview of the skull and layers of the scalp.

Embryonic origins, Developmental time course and Molecular Mechanisms / Factors / Genes are all blank, with no images to be seen.

Reference to a mouse model can be seen in the Animal models section, are there other models in other species of mouse mutant that can observe melanocyte embryology? Mention of the melanoma model of genetically-engineered mice is good, but how does it relate to neural crest abnormality?

Current Research explains 2 new systems to observe melanocytes, this section could show findings and how they're important - could be longer. Abnormalities listed are short, some missing entirely, more focus on which are more common could be longer. Abnormalities listed are short, some missing entirely, more focus on which are more common could be noted due to the vast nature of melanocytes. Glossary is nice but incomplete, and there are a sufficient number of references.

User:Z5113627

2018-10-02T09:03:27Z

Z5113627:

==Adrenal Gland and Neural Crest Cells==

{{Editing Links}}

==Reference List==

{{#pmid:30056110}}

In vitro maturation recent article {{#pmid:30056110|pmid:30056110}}

[[File:Neuropore cell shape changes.png|400px]]

Neuropore cell shape changes{{#pmid:30064364|PMID30064364}}

[[Help:Image Tutorial]]

<references/>

==Assessment==

===Melanocytes===

History of research is short, notes a few important researchers, lacks when melanocytes were connected to neural crest derivatives. It also lacks the knowledge of the role melanocytes play in human physiology and how that has changed, connection to Vitamin D synthesis and the history of the role melanocytes play in pathology could also be added.

Tissue Organ Structure and Function -
Skin is completely missing, no images or text to be seen.
Ear is well explained both in writing and images, understanding of chemical mediation in the adult has been elucidated, no reference to physiological role of the ear and how it achieves it, it would not have to be long. Figure 2 refers to Wv/Wv mutant, what is a Wv/Wv mutant? There is no explanation of this mutant model, whether it is in humans or animals, or why it is important etc.
Eyes section notes the combined role of neural-crest derived cells and neuroepithelium of optic cup, explains the layers of the eye nicely within the associated image of Figure 4, which has been correctly formatted and cited.
The heart section simply shows an image of a cardiac melanocyte, there should be more here.
The CNS topic is short, but it does note the understanding of a role of melanocytes in CNS, but nothing more about how neural crest cells help with giving melanocytes to the CNS, the image is a nice overview of the skull and layers of the scalp.

Embryonic origins, Developmental time course and Molecular Mechanisms / Factors / Genes are all blank, with no images to be seen.

Reference to a mouse model can be seen in the Animal models section, are there other models in other species of mouse mutant that can observe melanocyte embryology? Mention of the melanoma model of genetically-engineered mice is good, but how does it relate to neural crest abnormality?

Current Research explains 2 new systems to observe melanocytes, this section could show findings and how they're important - could be longer. Abnormalities listed are short, some missing entirely, more focus on which are more common could be noted due to the vast nature of melanocytes. Glossary is nice but incomplete, and there are a sufficient number of references.

===Cardiac===

Introduction - Short but does nicely explain some of the important aspects of cardiogenesis, the sentences could be ordered more cleanly and could allude to more than just animal models and their connection to neural crest and DiGeorge Syndrome in humans. History of knowledge of cardiogenesis maybe?

Development of the Cardiovascular System - Could possibly be retitled? (There is no mention of peripheral vasculature that is a part of the cardiovascular system, you have simply referred to cardiogenesis: the formation of the heart). The developmental timecourse is good at explaining the important events in cardiogenesis and what weeks they correspond to. The embedded video is also good, but is quite long at 9 minutes.

Cardiac Neural Crest Cells - This is a good introduction to the specific neural crest population that contribute to cardiogenesis. However, there are a few issues with sentence formatting, grammar and referencing that could be cleaned up. The mention of neural crest's pluropotentiality is perfect in understanding how the different tissue types of the valvular structures arise, so that is definitely a strong point of the section.

Early Development - Very good, key chemical mediators are mentioned, could more be explained about what they are and how they relate to neural crest specifically? An explanation on the circumpharyngeal ridge would also be welcomed.

Later Development - Very nice partitioning diagram, Valvulogenesis section could be longer, it is very important. The same can be said for Atrial and Ventricular Separation.

Signalling Molecules - Good overview, more links to literature would be appreciated than just Meis-2, more could be added if necessary to discussion.

Developmental Time Course appears incomplete.

Abnormalities - Seem quite well discussed, formatting needs some work as well as general cleaning with references, diagrams of a histology section or relevant macroscopic specimen would be welcome here to understand the pathology and how it relates to the embryology.

Research - Same as above, but there seems to be less information as well: there needs to be more content, directed referencing, images if necessary, and specific examples of mutant, knock-out or other genetically-engineered models to observe these embryological findings. There is good mention of the different animal models that are used to observe cardiogenesis (mouse, fish and chicken) but otherwise, it needs some work.

Glossary and References - Very few current references at the bottom, I assume this is because the bulk of them have not been formatted correctly, most appear to be from research literature and medical science journals, no current glossary might be an issue if there are many acronyms.

Talk:2018 Group Project 3

2018-10-02T02:46:25Z

Z5113627:

{{2018ANAT2341ProjectHeader}}
{{2018ANAT2341ProjectDiscussion}}


[[User:Z5229549|Z5229549]] ([[User talk:Z5229549|talk]]) 12:20, 14 August 2018 (AEST)
hi

[[User:Z5165679|Z5165679]] ([[User talk:Z5165679|talk]]) 12:20, 14 August 2018 (AEST)

[[User:Z5164785|Z5164785]] ([[User talk:Z5164785|talk]]) 12:20, 14 August 2018 (AEST)

[[User:Z5229132|Z5229132]] ([[User talk:Z5229132|talk]]) 12:21, 14 August 2018 (AEST)

Melanocytes

Development from neural crest

Areas found:
eyes
ears
heart
central nervous system meninges

Problems:
Hearing
Melanoma
vision

Intro

History

Embryonic origins

development time course

developmental/adult function

tissue/organ structure

molecular mechanisms/factors/genes

abnormalities/abnormal development

animal models

current research

glossary - useful when you have lots of acronyms. Be brief and clear
ref. list - generates itself as long as you ref. properly

needs to be explained to another uni student that doesn’t know anything about neural crest and its differentiation.

Key things to understand on what makes a good project page:
-Content
-Brevity and balance between text and images - it’s an online resource, not a textbook. BALANCE CONTENT.
-can have numbered lists and bullet points but don’t turn whole project into this.

If you can’t publish an image directly, you can redraw it and credit it to the article.

- differentiation
ho they get to different parts of the body
where the local singals come from etc
pigmentation and vitamin D

animal models

[[User:Z5229321|Z5229132]] ([[User talk:Z5229132|talk]]) 16:04, 04 September 2018 (AEST)
everyone on intro
z5229132 - history
z5165679 - animal models and current research
z5229549 - embryonic origins

=Assessment=

===Melanocytes===

History of research is short, notes a few important researchers, lacks when melanocytes were connected to neural crest derivatives. It also lacks the knowledge of the role melanocytes play in human physiology and how that has changed, connection to Vitamin D synthesis and the history of the role melanocytes play in pathology could also be added.

Tissue Organ Structure and Function -
Skin is completely missing, no images or text to be seen.
Ear is well explained both in writing and images, understanding of chemical mediation in the adult has been elucidated, no reference to physiological role of the ear and how it achieves it, it would not have to be long. Figure 2 refers to Wv/Wv mutant, what is a Wv/Wv mutant? There is no explanation of this mutant model, whether it is in humans or animals, or why it is important etc.
Eyes section notes the combined role of neural-crest derived cells and neuroepithelium of optic cup, explains the layers of the eye nicely within the associated image of Figure 4, which has been correctly formatted and cited.
The heart section simply shows an image of a cardiac melanocyte, there should be more here.
The CNS topic is short, but it does note the understanding of a role of melanocytes in CNS, but nothing more about how neural crest cells help with giving melanocytes to the CNS, the image is a nice overview of the skull and layers of the scalp.

Embryonic origins, Developmental time course and Molecular Mechanisms / Factors / Genes are all blank, with no images to be seen.

Reference to a mouse model can be seen in the Animal models section, are there other models in other species of mouse mutant that can observe melanocyte embryology? Mention of the melanoma model of genetically-engineered mice is good, but how does it relate to neural crest abnormality?

Current Research explains 2 new systems to observe melanocytes, this section could show findings and how they're important - could be longer. Abnormalities listed are short, some missing entirely, more focus on which are more common could be longer. Abnormalities listed are short, some missing entirely, more focus on which are more common could be noted due to the vast nature of melanocytes. Glossary is nice but incomplete, and there are a sufficient number of references.

User:Z5113627

2018-10-02T02:27:59Z

Z5113627:

User:Z5113627

2018-10-02T02:26:28Z

Z5113627:

2018 Group Project 1

2018-10-01T11:10:24Z

Z5113627: /* Genes and Transcription Factors Involved with the Adrenal Medulla's Development */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===
[[User:Z5014972|Z5014972]] ([[User talk:Z5014972|talk]]) 12:47, 14 August 2018 (AEST)z5014972
good review article https://link.springer.com/article/10.1007%2Fs12022-009-9070-6
----
===History===
----
'''Describing the neural crest'''

The "neural crest" is a term referring to the junction between the neural and epidermal ectoderm in the embryo. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. This change in the naming of the neural crest was due to the fact that two neural ridges could be seen on either size prior to the closure of the neural tube, resembling the appearance of a crest {{#pmid:19179766|PMID19179766}}.

[[File:NC Location.jpg|520px]]
''This figure shows the neural crest, a fold located between the epidermal ectoderm and the neural ectoderm. The neural ectoderm gives rise to the neural tube in the centre, the epidermal ectoderm, as the name suggests, gives rise to the skin and the neural crest is located between the two and gives rise to many other structures, tissues and organs in the body.''

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently. However, in the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many. This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest dos indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''

===Embryonic origins===
----

===Developmental time course===
----

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Developmental/adult function===
----
===Tissue/organ structure===

====Normal Structure and Function of the Adrenal Medulla====

The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The medulla contains secretory cells called chromaffin cells, due to the agents they produce when oxidised, such as chromate. These cells secrete epinephrine and norepinephrine in response to various substances such as acetylcholine.

There are three types of cells in the adult adrenal medulla:
1) Epinephrine cells
2) Norepinephrine cells
3) Small granule-containing cells (SGCs)
These cells also produce various other peptides such as substance P and neurotensin. The adrenal medulla also contains presynaptic sympathetic ganglion cells.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus.

[[File:Dd.jpg|500px|thumb|right|Adult Adrenal Glands in situ]]
----

===Molecular mechanisms/factors/genes===
----

====Role of Adrenal Medulla in the Neonate and Adult====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

>Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

>Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses.

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

Members of the SOX (SRY-Box) gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands.

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well.

[[File:Catecholamine_Synthesis.jpg|500px|thumb|right|Cascade of Catecholamine Synthesis]]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291442/
https://www.ncbi.nlm.nih.gov/pubmed/19396395

===Abnormalities/abnormal development===
----
===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Prenatal adrenal gland development has been described in a number of scientific reports dating from the 1900s to studies in more recent years. These involved a variety of animal models such as ox, sheep, swine and most commonly mice.

Prenatal adrenal gland development has been described in numerous published reports covering a wide variety of species, including the ox (Katznelson, 1966; Wrobel and Suss, 1999), sheep (Davies, 1950; Wintour et al., 1975; Upadhyay and Zamboni, 1982; Naaman‐Reperant and Durand, 1997; Grino, 2004), swine (Sokolov et al., 2006) and mouse (Waring, 1935; Ikeda et al., 1994; Sass, 1996; Nyska and Maronpot, 1999; Bland et al., 2003; Val et al., 2007). Adrenal gland development also has been extensively described for humans as well (Kolliker, 1879; Minot, 1892; Zuckerkandl, 1912; Wieman, 1920; Ikeda et al., 1981; Langlois et al., 2002; Hanley and Arit, 2006).

https://www.sciencedirect.com/science/article/pii/S0925477302004550
http://dev.biologists.org/content/develop/126/13/2935.full.pdf

===Current research (labs)===
----
Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2α, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/

===Glossary===
----
===Reference list===

File:Catecholamine Synthesis.jpg

2018-10-01T11:04:58Z

Z5113627: A simplified biochemical cascade of Catecholamines from L-Tyrosine onwards. Legend: C - Carbon N - Nitrogen H - Hydrogen O - Oxygen ⌬ - Benzene group z5113627 Beginning six months after publication, I (z5113627) grant the public the non-exclusiv...

A simplified biochemical cascade of Catecholamines from L-Tyrosine onwards.

Legend:

C - Carbon
N - Nitrogen
H - Hydrogen
O - Oxygen
⌬ - Benzene group

z5113627

Beginning six months after publication, I (z5113627) grant the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode."

2018 Group Project 1

2018-09-29T11:21:05Z

Z5113627: /* Genes and Transcription Factors Involved with the Adrenal Medulla's Development */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===
[[User:Z5014972|Z5014972]] ([[User talk:Z5014972|talk]]) 12:47, 14 August 2018 (AEST)z5014972
good review article https://link.springer.com/article/10.1007%2Fs12022-009-9070-6
----
===History===
----
'''Describing the neural crest'''

The "neural crest" is a term referring to the junction between the neural and epidermal ectoderm in the embryo. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. This change in the naming of the neural crest was due to the fact that two neural ridges could be seen on either size prior to the closure of the neural tube, resembling the appearance of a crest {{#pmid:19179766|PMID19179766}}.

[[File:NC Location.jpg|520px]]
''This figure shows the neural crest, a fold located between the epidermal ectoderm and the neural ectoderm. The neural ectoderm gives rise to the neural tube in the centre, the epidermal ectoderm, as the name suggests, gives rise to the skin and the neural crest is located between the two and gives rise to many other structures, tissues and organs in the body.''

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently. However, in the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many. This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest dos indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''

===Embryonic origins===
----

===Developmental time course===
----

The adrenal gland has two distinct sections, the cortex and the medulla, both with different embryonic origins. The cortex accounts for 90% of the adrenal glands and arises from intermediate mesoderm. The medulla only accounts for 10% of the adult adrenal glands, however it has neural crest embryonic origin. The medulla consists of chromaffinoblast cells which are migrant neuroblast cells from the neural crest, therefore the adrenal medulla is a component of the sympathetic nervous system.{{#pmid:21175739|PMID21175739}} Neural crest cells replicate in week 7 and begin to differentiate in week 8, the cells then migrate to the developing adrenal gland in week 9 of development.{{#pmid:25255746|PMID25255746}}{{#pmid:18279781|PMID18279781}} The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.{{#pmid:23354096|PMID23354096}} Throughout development the cells will become more compact in the centre of the gland, during this period of development the adrenal gland is growing rapidly. The gland is abnormally large until the second trimester and the medulla is much thicker prenatally.{{#pmid:18279781|PMID18279781}}{{#pmid:21175739|PMID21175739}}

===Developmental/adult function===
----
===Tissue/organ structure===

====Normal Structure and Function of the Adrenal Medulla====

The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The medulla contains secretory cells called chromaffin cells, due to the agents they produce when oxidised, such as chromate. These cells secrete epinephrine and norepinephrine in response to various substances such as acetylcholine.

There are three types of cells in the adult adrenal medulla:
1) Epinephrine cells
2) Norepinephrine cells
3) Small granule-containing cells (SGCs)
These cells also produce various other peptides such as substance P and neurotensin. The adrenal medulla also contains presynaptic sympathetic ganglion cells.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus.

[[File:Dd.jpg|500px|thumb|right|Adult Adrenal Glands in situ]]
----

===Molecular mechanisms/factors/genes===
----

====Role of Adrenal Medulla in the Neonate and Adult====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

>Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

>Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses.

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

Members of the SOX (SRY-Box) gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

Mouse models have demonstrated that SOX-10 knock-outs (mice whose DNA has been engineered to not express SOX-10) do not have an adrenal medulla. There has also been suggestion that SOX-8,9 and 10 are all strongly related to the migratory patterning of neural crest cells to the developing adrenal glands.

The TH gene (for Tyrosine Hydroxylase) encodes the aforementioned enzyme in the adrenal medulla and central nervous system. Tyrosine Hydroxylase is crucial in biochemical pathways and cascades for the synthesis of catecholamines and other CNS neurotransmitters. The conversion from L-Tyrosine to L-DOPA is dependent upon the catalytic action of Tyrosine Hydroxylase. From there, L-DOPA can make Dopamine and eventually Epinephrine and Norepinephrine as well.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291442/
https://www.ncbi.nlm.nih.gov/pubmed/19396395

===Abnormalities/abnormal development===
----
===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Two of the most common animals used in the research regarding embryology is the chicken and mouse embryos, for their similarity to human embryos, ease of reproduction (allowing for a large specimen bank), ease of handling, cost effective and there are also no ethical issues limiting its use.

Prenatal adrenal gland development has been described in numerous published reports covering a wide variety of species, including the ox (Katznelson, 1966; Wrobel and Suss, 1999), sheep (Davies, 1950; Wintour et al., 1975; Upadhyay and Zamboni, 1982; Naaman‐Reperant and Durand, 1997; Grino, 2004), swine (Sokolov et al., 2006) and mouse (Waring, 1935; Ikeda et al., 1994; Sass, 1996; Nyska and Maronpot, 1999; Bland et al., 2003; Val et al., 2007). Adrenal gland development also has been extensively described for humans as well (Kolliker, 1879; Minot, 1892; Zuckerkandl, 1912; Wieman, 1920; Ikeda et al., 1981; Langlois et al., 2002; Hanley and Arit, 2006).

===Current research (labs)===
----
===Glossary===
----
===Reference list===

2018 Group Project 1

2018-09-27T06:14:32Z

Z5113627: /* Tissue/organ structure */

=The Contribution of Neural Crest Cells to the Adrenal Medulla=
----
{{2018ANAT2341ProjectHeader}}


===Introduction===
[[User:Z5014972|Z5014972]] ([[User talk:Z5014972|talk]]) 12:47, 14 August 2018 (AEST)z5014972
good review article https://link.springer.com/article/10.1007%2Fs12022-009-9070-6
----
===History===
----
'''Describing the neural crest'''

The "neural crest" is a term referring to the junction between the neural and epidermal ectoderm in the embryo. The neural crest contributes a large number of cells of varying structure and function that directly or indirectly contribute to the development of tissues and organs within the body {{#pmid:19179766|PMID19179766}}. In 1868, the neural crest cells were first identified in a chick embryo as a collection of cells known as "Zwischenstrang" by Professor Wilhelm His {{#pmid:22820859|PMID22820859}}. Wilhelm His was among the first to provide an explanation for the mechanics governing the developing embryo as well as the physiology and the organs that the differing germinal regions would eventually give rise to. In 1878, the term neural ridge was used to describe this collection of cells but the term neural crest was later coined by Arthur Milnes Marshall in 1879 in a paper he worked on disseminating the knowledge from his research on the development of cranial nerves in chicken embryos. This change in the naming of the neural crest was due to the fact that two neural ridges could be seen on either size prior to the closure of the neural tube, resembling the appearance of a crest {{#pmid:19179766|PMID19179766}}.

[[File:NC Location.jpg|520px]]
''This figure shows the neural crest, a fold located between the epidermal ectoderm and the neural ectoderm. The neural ectoderm gives rise to the neural tube in the centre, the epidermal ectoderm, as the name suggests, gives rise to the skin and the neural crest is located between the two and gives rise to many other structures, tissues and organs in the body.''

'''1890s-1950s'''
The neural crest is the point of origin for spinal/cranial ganglia and neurons. This theory received little criticism and was not contested much by other researchers prior to the 1890s. This is owing to the fact that the neural crest is quite closely related to the neural tube and thus this relationship makes sense. This discovery was made by His and Marshall, however, they found this out independently. However, in the 1890s, Julia Platt, claimed that odontoblasts as well as the cartilages forming the facial and pharyngeal arch skeletons came from the ectoderm. This created much debate and was contested by many. This is because this theory completely contradicted the germ-layer theory, whereby skeletal tissues originate at the mesoderm and not the ectoderm. The controversies this finding brought about a slowing down of research, as demonstrated by a gap of almost 40 years between the theory that skeletal tissues originating from the neural crest. Today, it is known that the neural crest dos indeed play a role in the development of the skeleton in vertebrates, particularly, the cranial neural crest. Although these studies were occurring, the focus was still primarily on researching pigment cells and ganglia of the spine up until the 1950s, when Sven Hörstadius' major work on the neural crest was published, titled "The Neural Crest: Its properties and derivatives in the light of experimental research". This work focused on experimental data tracing the development of the cartilaginous skeleton derived from the neural crest {{#pmid:19179766|PMID19179766}}.

'''1960s - 1970s'''

===Embryonic origins===

===Developmental time course===
----

{{#pmid:21175739|PMID21175739}}
- The adrenal gland, consisting of a cortex and a medulla, with each component arising from different embryonic origins.
- The adrenal cortex arises from intermediate mesoderm.
- The medulla is composed from chromaffinoblast cells of neural crest origin, which migrate.
- Medulla much thicker prenatally.
- The migrant neuroblast cells infiltrate the adrenal cortex as sympathochromaffin cells from the neural crest.

{{#pmid:23354096|PMID23354096}}
- Initially the chromaffin cells are scattered as islands in the cortex
- Adrenal gland grows rapidly after second month

{{#pmid:18279781|PMID18279781}}
- Week 9 neural crest cells migrate
- Until third trimester adrenal gland is abnormally large
- Medulla part of sympathetic nervous system
- Medulla 10% adult mesoderm
- From neuro-ectoderm – modified sympathetic ganglion

{{#pmid:25255746|PMID25255746}}
- Neural crest cells = primitive sympathetic cells/paraganglionic cells, of ectodermal origin, have nerve tracts, week 7 replicate and differentiate by week 8

===Developmental/adult function===
----
===Tissue/organ structure===

====Normal Structure and Function of the Adrenal Medulla====

The cells of the adrenal medulla are derived from the neural crest as opposed to the mesodermal origins of the cortex. The medulla contains secretory cells called chromaffin cells, due to the agents they produce when oxidised, such as chromate. These cells secrete epinephrine and norepinephrine in response to various substances such as acetylcholine.

There are three types of cells in the adult adrenal medulla:
1) Epinephrine cells
2) Norepinephrine cells
3) Small granule-containing cells (SGCs)
These cells also produce various other peptides such as substance P and neurotensin. The adrenal medulla also contains presynaptic sympathetic ganglion cells.

====Related Anatomy====

The tissue and organ structure of the adrenal medulla should be understood with regard to its specialised function within the sympathetic nervous system.

The medullary region of the adrenal glands is tasked with the endocrine secretions of adrenaline and nor-adrenaline in response to environmental stressors that are signalled for by the sympathetic nervous system. That is, the secretion of fight-or-flight response hormones in order to restrict vasculature to the trunk and increase vascular activity in the peripheral musculature.

The adrenal glands are supplied by several branches of the great vessels in the abdominal cavity. The secreted catecholamines in the medulla are directly able to pass to the blood stream this way.

These adrenal glands and their contents are retroperitoneal in the adult and varied in shape, with the left often being semilunar and right being pyramidal. Nervous supply of the adrenal glands is achieved by contributions from the splanchnic nerves of the celiac plexus.

[[File:Dd.jpg|500px|thumb|right|Adult Adrenal Glands in situ]]
----

===Molecular mechanisms/factors/genes===
----

====Role of Adrenal Medulla in the Neonate and Adult====

Understanding the biochemistry of catecholamines is necessary to see how the adrenal medulla is designed in the stages of embryology and how it is suited for life in the neonate and adult.

The epinephrine and norepinephrine in the neonate and adult work by primarily changing the osmoregulatory state of vasculature in organs. With the exclusion of their neuromodulatory and neurotransmitter functions, epinephrine and norepinephrine are mainly tasked with the control of sympathetic and parasympathetic supplies.

>Norepinephrine is a constrictor of peripheral vasculature by antagonising the action of surface receptors expressed on the endothelium of blood vessels, specifically Alpha-1 and Alpha-2 receptors, such that vascular resistance increases.

>Epinephrine is both a vasoconstrictor and vasodilator, depending on what receptors it attaches to. As a non-selective adrenergic agonist, it acts on Alpha-1, Alpha-2, Beta-1, Beta-2 and Beta-3 receptors that are found throughout the body's tissues, yielding many different physiological responses.

====Genes and Transcription Factors Involved with the Adrenal Medulla's Development====

Members of the SOX (SRY-Box) gene family have multiple key contributors to Neural Crest in the Adrenal Medulla.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291442/
https://www.ncbi.nlm.nih.gov/pubmed/19396395

===Abnormalities/abnormal development===
----
===Animal models===
----
Animal models are an integral part of research in embryology. In particular due to the moral concerns regarding the use of humans in scientific research. As a result different animals are used as substitutes to simulate the same environments and hope to achieve results that would also be able to represent humans as well. Two of the most common animals used in the research regarding embryology is the chicken and mouse embryos, for their similarity to human embryos, ease of reproduction (allowing for a large specimen bank), ease of handling, cost effective and there are also no ethical issues limiting its use.

Prenatal adrenal gland development has been described in numerous published reports covering a wide variety of species, including the ox (Katznelson, 1966; Wrobel and Suss, 1999), sheep (Davies, 1950; Wintour et al., 1975; Upadhyay and Zamboni, 1982; Naaman‐Reperant and Durand, 1997; Grino, 2004), swine (Sokolov et al., 2006) and mouse (Waring, 1935; Ikeda et al., 1994; Sass, 1996; Nyska and Maronpot, 1999; Bland et al., 2003; Val et al., 2007). Adrenal gland development also has been extensively described for humans as well (Kolliker, 1879; Minot, 1892; Zuckerkandl, 1912; Wieman, 1920; Ikeda et al., 1981; Langlois et al., 2002; Hanley and Arit, 2006).

===Current research (labs)===
----
===Glossary===
----
===Reference list===