2018 Group Project 1

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The Contribution of Neural Crest Cells to the Adrenal Medulla

Projects 2018: 1 Adrenal Medulla | 3 Melanocytes | 4 Cardiac | 5 Dorsal Root Ganglion


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.


Describing the neural crest

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[1]. 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 [2]. 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 [3]. 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. [2].

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[3].

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 [2].

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 [2]. 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 [3]. The cells in the trunk neural crest that migrate vertically become the sympathetic ganglia, the nerves proximal to the aorta and the adrenal medulla [4]. 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 [2].

1980s - 21st century

Neural crest regions

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 [2]. The vagal & sacral neural crest gives rise to the parasympathetic ganglia found in the gut. Without these ganglia, peristalsis, is not possible [4]. The cardiac neural crest contributes to the valves, septa and major blood vessels of the heart, as well as connective tissues and cartilage[2]. 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 [4].

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 [2]. 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 [1].

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 [1].

Developmental time course

Adrenal Medulla Developmental Timeline.jpg

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.[5] 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.[6][7] The neural crest cells infiltrate the cortex and the chromaffin cells are scattered islands in the cortex.[8] 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.[7][5]

Embryonic origins

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 [9]. Specifically, this neural crest tissue comes from the trunk neural crest cells (see above figure to determine the approximate location in an embryo) [4]. 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 [10]. The trunk neural cells arise caudally, undergo an epithelial to mesenchymal transition and follow three migratory pathways [11].

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 [4]. - A ventrolateral pathway (through the somites) - A ventromedial pathway (between neural tube and posterior schlerotome)[11].

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 [12]. Chromaffin cells are neuroendocrine cells and are found in the sympathetic ganglia and make up the majority of the adrenal medulla[12]. 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 [12].

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 [4]. 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 [12]. 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 [13].

Developmental/adult function

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 [14]. 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 [15]. 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 [14]. 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 [15].

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 [16]. 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 [17]. 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 [18]. 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 (18). The adrenal medulla thus appears to provide vital physiological functions for fetal and neonatal survival, especially during birth.

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. [19]

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. [20]

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. [21]

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. [22]
  • 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
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. [23]

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. [21]

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




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[24]. 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[25]. 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[26]. After 16 days it was observed that a capsule had formed in some parts and TH - positive cells had penetrated the adrenal gland[26]. 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[27]. 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[28]. Previous research had shown that BMP - 4 a growth factor is plays an important role in the regulation of chromaffin cell production[29]. 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[28]. 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[30]. 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://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768882/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693940/


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