2012 Group Project 4

From Embryology
Revision as of 23:58, 14 September 2012 by Z3333038 (talk | contribs) (→‎Treatment)

Olfaction Development

Introduction

Cribiform plate and Olfactory Bulb/Epithelium

.

The sense of smell, or otherwise known as Olfaction is the sense mediated by sensory cells located in the nasal cavity. Chemoreceptors within the naval cavity are activated by chemicals in the air which are known as odorants. Odorants produce olfactory sensation at very low concentration, and through the reaction with chemoreceptors enables the sense of smell in humans. The olfactory system are often divide into a peripheral mechanism, activated by an external stimulus and transforming it into an electric signal in neurons, and a central mechanism where all signals formed by olfactory are integrated in the central nervous system and processed to recognise odor. Over 1000 genes which make up three percent of the total human genome which encode for olfactory receptor types which can each detect a small number of related molecules and respond with different level of intensity. It has been discovered that olfactory receptor cells are highly specialized to particular odors.

History of Discovery

Julius Kollmann

Julius Kollmann was revolutionary and prominent German scientist from the late 1800s, early 1900s. He was involved in a wide variety of fields ranging from anatomy, to anthropology[1]. He published a textbook called the Atlas of the Development of Man 2 in 1907. Included in this textbook were a great number of diagrams depicting olfactory development. For example a diagram of the riechpiakode, the olfaction placode, which Kollmann explains that the placode is formed from multiple layers of ectoderm[2]

Alt
Diagram of developing nasal placode

Anthony A. Pearson

Anthony A. Pearson conducted a study in 1941 examining serial sections of human embryos to understand the development of the olfactory nerve. It was seen the cells migrate from the olfactory epithelium up obliquely toward the brain collecting as fibers. His research indicated that olfactory nerve fibers start to form communications with the brain six weeks into development. He also asserted that the olfactory bulb starts to form in a 17mm embryo following which the proximal end of the olfactory nerve forms a sheath of fibers over the bulb. The fibers of this sheath collect together and continue to develop to form the fila olfactoria which eventually pass through the cribriform plate[3]

The 2004 Nobel Prize in Physiology or Medicine was won by Linda B. Buck and Richard Axel for their work on the olfactory system[4]

Timeline of developmental process

Week/Stage Description Image
Week 4

All five facial swellings form initially surrounding the stomodeum.

The frontonasal prominence is the facial swelling which gives rise to olfactory placodes. It overlies the forebrain and arises from neural crest cells derived from midbrain and forebrain. [5]

Like the majority of placodes, some mesenchymal cells migrate away from the placodal epithelium and differentiate as either secretory cells or glial cells.[6]

Some specialised areas in the rostrolateral regions of the head of the olfactory placode contain cells of cranial non-neural ectoderm. These cells differentiate to form the primary neurosensory cells of the future olfactory epithelium. This differentiation is a cuboidal-to-columnar transformation and so are distinguishable from the surrounding cuboidal epithelium.

image

Week 5

As the paired maxillary prominences enlarge and grow ventrally and medially, the ectodermal thickenings of the olfactory placode enlarge.

At the end of the 5th week, the primary neurosensory cells cells sprout axons that cross the short distance to penetrate the most cranial end of the telencephalon. The subsequent endochondral ossification of the ethmoid bone around these axons creates the perforated cribriform plate.

Image

Week 6

The ectoderm at the center of each nasal placode invaginates to form an oval nasal pit, dividing the frontonasal prominence into the lateral and medial nasal processes. At the end of the 6th week, as the medial nasal processes start to merge, the dorsal region of the deepening nasal pits fuse to form a single, enlarged ectodermal nasal sac lying super posterior to the intermaxillary process. The nasal pits differentiate to form the epithelium of the nasal passages.

Nasolacrimal groove:This groove forms between the lateral nasal process and the adjacent maxillary prominence.

The medial nasal processes migrate toward each other and fuse to form the primordium of the nasal bridge and nasal septum.

Olfactory bulb growth: An outgrowth is formed where the axons of the primary neurosensory cells synapse,this is seen at the floor at each cerebral hemisphere. The synpasing cells differentiate to become the secondary sensory neurons, mitral cells, of the olfactory pathways.

Olfactory nerve formation: formed due to the lengthening of the axons of the mitral cells as the proportions of the face and brain lenghthens. As a result, the CNS olfactory tracts look stalk-like. Olfactory nerve: the olfactory tract and bulb together.

Image

Week 7

Nasolacrimal duct and sac: The ectoderm at the floor of the nasal pit invaginates into the underlying mesenchyme. The duct becomes lined by bone during the ossfication of the maxilla After birth, it functions to drain excess tears from the conjunctiva of the eye into the nasal cavity.

Intermaxillary process: The inferior tips of the medial nasal processes expand laterally and inferiorly and fuse.

Separation of nasal and oral cavity: The floor and posterior wall of the nasal sac proliferate to form thickened ectoderm, Nasal fin.

Oronasal Membrane: The sac enlarges as vacuoles develop within the nasal fin which fuse with the nasal sac. As a result of this, the nasal fin thins and is labelled as the oronasal membrane

Primitive choana: formed as the oronasal membrane ruptures.

The floor of the nasal cavity at this stage is formed by a posterior extension of the intermaxillary process called the primary palate. Palatal sheleves will later form to separate the two cavities.


word linked to glossary

Image

Week 8

Nasal septum and philtrum:Ectoderm and mesoderm of the frontonasal prominence and the medial nasal processes proliferate and grows down from the roof of the nasal cavity to fuse with the upper surface of the primary and secondary palates along the midline .

image




SINUSES: A:

EFFECT OF AMNIOTIC FLUID ON THE DEVELOPMENT OF OLFACTION IN THE FETUS (current research in the field):

[7]

Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.

Structure

Olfactory Bulb

Anatomy and Physiology of Olfaction

Normal Function

Olfactory Signal Transduction

The sensation of smell is dependent upon the dissolving of substances known as odorants in the mucus layer of the olfactory epithelium in order to bind to specific chemoreceptors. This step is necessary otherwise olfactory signal transduction is not possibly through the olfactory nerve. The olfactory epithelium, also known as the organ for smell is located at the roof of the nasal cavity.

When odorant molecules bind to receptors in olfactory epithelium, a G protein known as G(olf) is activated which then happen to activate adenylate cyclase, an enzyme which catalyses the formation of cyclic AMP. In most receptor cells, cAMP acts as a second messenger, however in the olfactory system cAMP bind to cation channels which permits sodium and calcium ions to travel through the membrane and enter the cell. The main effect of ion entry into the cell is depolarisation, and if the depolarization is great enough, an action potential is generated on the axon of the receptor cell. [8]

Olfactory Epithelium

The Neurology of Smell

The Neurobiology of Olfaction

Olfactory System

Congenital Abnormalities

Anosmia

Kallmann's Syndrome

Introduction and Epidemiology

Kallmann's syndrome is a clinically and genetically heterogeneous disorder, described as a hypogonadotropic hypogonadism characterized by a diminished or absent sense of smell [9] [10]. The incidence of Kallmann's syndrome is uncertain but is estimated to occur in 1 in 10,000 to 1 in 50,000 people [11], affecting males to females in a 5:1 ratio [12]. Anosmia or hyposmia occurs as a results of impaired development of the olfactory bulbs and olfactory nerves [12]. Additionally, hypogonadism results due to the reduced production of Gonadotropin-releasing hormone (GnRH). Kallmann's syndrome can be inherited as an autosomal dominant,autosomal recessive trait, or an X-linked recessive trait [12].

Pathophysiology

The olfactory bulb is the first neuronal checkpoint for olfactory information[13]. The OB receives and processes sensory inputs from olfactory receptor neurons embedded in the olfactory epithelium and then transmits the information to the olfactory cortex[13]. During embryonic development, axons from olfactory receptor neurons exit the olfactory epithelium, grow toward the brain, and penetrate the OB where they synapse with the dendrites of mitral cells [13]. The axons of these neurons form the olfactory tract.

Olfactory Neuronal Migration in Kallmann's Syndrome

In Kallmann's syndrome, there are distinct abnormalities in the OB development arising due to the abnormal or lack of expression of certain proteins and genes. Kallmann's syndrome can be X-linked , autosomal dominant or autosomal recessive[12]. To date, mutations the six genes and the proteins they encode have been attributed to Kallmann's syndrome. However, only 30% of patients with a clinical diagnosis are found to have a mutation in these genes [14]:

  • KAL1: Mutations in the KAL1 gene produce the X-linked form of Kallmann's syndrome. KAL1 gene encodes the glycoprotein anosmin 1 [15].
  • KAL2 (FGFR1): Produces the autosomal-dominant form of Kallmann's syndrome. KAL2 encodes fibroblast growth factor receptor 1 [16].
  • PROK2
  • PROKR2
  • FGF8
  • CHD7

Clinical Features

Kallmann's Syndrome is a congenital hypogonadotropic hypogonadism (HH)[9]. Kallmann's Syndrome has the classical HH absence of puberty but is distinguished from other HH syndromes by an affected sense of smell. There exists additional characteristics that are not specific to Kallmann's syndrome but may aid in correct diagnosis of this particular HH [17]. The following characteristics of Kallmann's syndrome may be present or not present in different cases, often varying according to genotype [9]:

Reproductive Features


Non-Reproductive Features

Diagnosis

Due to the low incidence of Kallmann's syndrome, correct diagnosis is often delayed, despite early childhood signs such as anosmia and cryptorchidism [24]. Instead, doctors often dismiss Kallmann's syndrome as constitionally delayed puberty [24]. Other differential diagnoses include potential presence of hypothalamic or pituitary tumours[24]. Due to the varied phenotype and genotype of Kallmann's, multiple tests are required in order to properly diagnose the syndrome. The following diagnostic tests are often employed:

  • Olfactory tests
  • Haematological testing for low serum testosterone (males) or oestrogen (females) and low levels of the gonadotropins LH and FSH
  • Physical examination and the Tanner Scale: a criterion which defines the stage of puberty the patient is in based on external primary and secondary sexual characteristics idism [14]
  • Magnetic resonance imaging: utilised to examine the olfactory bulb as well as rule out neoplasms in the hypothalamus or pituitary gland as the cause of abnormal or reduced GnRH secretion [14]. In Kallmann's syndrome, olfactory bulb is either not present or not fully developed [14]
  • Genetic screening for mutations in genes associated with Kallmann's syndrome; however, negative result does not rule out possibility of the syndrome [14].


Treatment

  • Fertility treatment
  • Hormone replacement therapy: testosterone injections (males), oestrogen and progesterone pills (females), GnRH injections.
  • Treatment to prevent osteoporosis: HRT and vitamin D supplementation [25].

Current Research

Olfactory Systems Laboratory

Contribution of Neural Crest and Ectoderm to Nasal Placode

A paper published last year explored the individual neural crest and ectodermal contributions to the nasal placode through the use of genetic Cre-lox tracing in two mice species. One mouse species was Wnt1Cre, a neural-crest specific line. The other species was Crect, an ectodermal specific line. The Cre-lox genetic tracing of the two species determined that olfactory ensheathing cells are neural crest in origin. Neural crest was also shown to contribute to cells of the olfactory epithelium and vomernasal organ along with GnRH-1 neurons. The findings of this paper allowed provided an understanding of the link relating neural crest defects to diseases such as anosmia and Kallmann syndrome[26].

Contribution of Cranial Neural Crest to Olfactory System

Alt
Contribution of Cranial Neural Crest to Olfactory System - Neural crest-derived cells in the embryonic olfactory epithelium

Another paper also investigating the contribution of cranial neural crest cells in olfaction development used transgenic mice. The neural crest cells of these mice permanently express green fluorescent protein (GFP) which allowed them and their descendants to be traced. Analysis showed GFP-positive cells in the olfactory epithelium, olfactory ensheathing cells . Similar analysis of chick embryos demonstrated dissociated cells of the olfactory mucosa which displayed the ability to self-renew, suggesting the presence of neural crest progenitors in the olfactory mucosa. The paper concluded that the cranial neural crest contributed a larger portion than previously thought to the olfaction system and may be accountable for the olfactory epithelium’s ability to regenerate[27].

Specialisation of Olfactory Bulb and Epithelium Reliant on Specific Genes

A study from August this year looked into the effect of genes Neurog1 and Neurog2 on cell specialisation in the olfactory bulb and olfactory epithelium. It was concluded that Neurog1 and Neurog2 are both necessary for the development of the olfactory system and are reliant on interactions between the olfactory bulb and olfactory epithelium. One particular part of the research looking to determine whether Neurog1 and Neurog2 were required for olfactory bulb development utilised a loss-of-function technique to compare single and double null mutants. It was concluded that Neurog1 is required for correct growth and lamination of the olfactory bulb and that Neurog1 and Neurog2 are required for overall bulb morphogenesis[28].

Migratory Path of GnRH

Another paper also published this year examined the migratory path of Gonadtropin-releasing hormone (GnRH) neurons and how this path is modulated by members of the Slit-Robo group of ligand ligand-receptors. Gonadtropin-releasing hormone neurons originate in the nasal placode and migrate by the olfactory and vomernasal axons to the hypothalamus in the forebrain. GRH is responsible for regulation of reproduction in mammals. Deficiency in it causes hyopgonadotropic hypogonadism and Kallmann syndrome. The current study used genetically altered mouse models to demonstrate the role of Slit2 and Robo3 in GnRH migration. Mice lacking Slit2 were found to have fewer GnRH neurons compared to wild type mice with Slit2[29]

SEMA3A deletion and Kallmann syndrome

A recent study[30] published in the Oxford Medicine's Human Reproduction Journal sought to identify new genes responsible for Kallmann's syndrome(KS) by conducting a comparative genomic hybridization array on KS patients with no mutations in known KS genes. A family with a history of KS was involved in the study and lead to the discovery of a heterozygous deletion at locus 7q21.11. Further investigation found that this was a deletion of the gene SEMA3A. SEM3A codes for semaphorin 3A, a protein that interacts with neuropilins: transmembrane glycoprotein receptors in neurons[30]. Moreover, analysis of the pattern of KS incidence in the family in conjunction with genetic testing found the mutation to be autosomal dominant[30]. In order to consolidate the link between SEMA3A deletion and KS, the study looked to the literature. It was found that studies with semaphorin 3A-knockout mice have a KS phenotype: abnormal migration of GnRH neurons to the hypothalamus as a result of faulty signal transduction[30].

Colony Stimulation Factor-1 Receptor and Embryonic Olfactory Development

A study by Erblich et al. [31] sought to study the transmembrane tyrosine kinase receptor for colony stimulating factor-1 (CSF-1R). Mice homozygous for a null mutation (-/-) in the Csflr gene as well as mice homozygous for non-mutated Csflr (+/+) were utilised to study CSF-1R function. Antibody staining for CSF-1R showed expression of CSF-1R in the microglia but not in the astrocytes, neurons or glial cells. In contrast, the -/- mice showed no CSF-1R expression. Moreover, cell counts showed that in -/- mice, the microglial numbers declined within three weeks of birth. The microglial depletion in -/- mice was accompanied by abnormal structural integrity of the brain: whilst the brain size remained normal, there was significant ventricular enlargement with reduced parenchymal volume. From these findings, it is apparent that CSF-1R has an importnt role in microglial development and normal brain architecture. In regards to the olfactory bulb, there was an apparent reduction in size for the -/- mice but no obvious change in structure. However, the olfactory bulb was hollowed out in the -/- mice as a result of enlargement of the cerebrospinal fluid compartment impinging onto the olfactory ventricle. Testing for olfactory deficits revealed that an absence of Csf1r gene is anosmic. These findings show that CSF-1 is required for the function and integrity of the olfactory system.[31]

Lhx2-dependent Integration of Olfactory, Vomeronasal, and GnRH Neurons

When the LIM-homeodomain 2 gene (Lhx2) is normally expressed in the forebrain, the olfactory bulb, as well as in olfactory sensory neurons (OSNs) and vomeronasal sensory neurons (VSNs)[32]. When Lhx2 is not expressed, specification of olfactory sensory neurons (OSNs) becomes abnormal[32]. A study [32] published in 2012 sought to identify the exact consequences of absent Lhx2-dependent OSN specification on the development of the primary olfactory pathway. The method involved utilising transgenic mice with inactivated Lhx2 gene in OSNs but not in VSNs the olfactory bulb, or the forebrain. The study found that Lhx2-dependent OSN specification is essential for synapses between OSN and target neurons in the olfactory bulb. Moreover, the mutant phenotype showed that expansion of the olfactory bulb is dependent on innervation of the bulb by OSNs expressing Lhx2. Additionally, Lhx2-dependent maturation of OSNs is required for formation of the vomeronasal nerve and the migration of gonadotropin-releasing hormone (GnRH) cells toward the developing hypothalamus. The implications of these findings to olfactory research are a further understanding of the innervation mechanisms of the olfactory bulb during development. Moreover, the findings of the study can aid in understanding congenital olfactory defects.

Glossary

Aplasia: Absent development of an organ or tissue.

Anosmia: Lack of smell.

Cerebellar ataxia: Reduced control over muscle coordination arising from defects or damage to the cerebellum.

Cryptorchidism: Failure of one or both testes to migrate into the scrotum during male foetus development.

Eunuchoidism: Male hypogonadism characterised by the failure of the testes to develop and an absence of secondary sexual characteristics.

Gynaecomastia: The development of abnormal mammary glands in males characterised by enlarged breasts.

Hypogonadism: A state which described reduced or absence of hormone secretion by the gonads (ovaries or testes).

Hypogonadotropism: Reduced or absent gonadotropin secretion, often characterised by FSH and LH deficiency leading to testicular or ovarian dysfunction.

Hypoplasia:Incomplete development of an organ or tissue.

Nystagmus: Refers to fast involuntary movements of the eyes that may impair vision. Can be described as a "rapid flicking side to side" movement.

Olfactory bulb: The primary part of brain which processes olfactory information.

Olfactory epithelium: mucous membrane superior to the nasal cavity which contain olfactory nerve cells.

Olfactory nerve cell: Cells in the olfactory epithelium which detect various odors and signal the information to the CNS.

Pheromone: Any molecules (scent) released by animals and affect the behavior of organisms of the same species via the olfactory system.

Pes cavus: A deformity of the foot characterised by an overexaggerated arch and hyperextension of the toes. Also referred to as clawfoot.

Spastic paraplegia: A hereditary paraplegia characterised by stiffness and contraction in the lower limbs as a result of neuronal dysfunction.

Synkinesia: Refers to the ability to conduct voluntary movements, however, with accompanied involuntary muscular movements.

References

  1. <pubmed>3548583</pubmed>
  2. Kollmanm, J. (1907). Atlas of the Development of Man (Vol. 2). Germany. Sourced from http://embryology.med.unsw.edu.au/embryology/index.php?title=Main_Page
  3. A A Pearson The Development of the Olfactory Nerve in Man J. Comp. Neurol.:1941, 75(2);199-217
  4. http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/press.html
  5. <pubmed>21882426</pubmed>
  6. <pubmed>16677629</pubmed>
  7. Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
  8. <pubmed>21882432</pubmed>
  9. 9.0 9.1 9.2 <pubmed>22882983</pubmed>
  10. <pubmed>6932275</pubmed>
  11. <pubmed>16952059</pubmed>
  12. 12.0 12.1 12.2 12.3 <pubmed>21682876</pubmed>
  13. 13.0 13.1 13.2 <pubmed>12007408</pubmed>
  14. 14.0 14.1 14.2 14.3 14.4 <pubmed>20949504</pubmed>
  15. <pubmed>1913827</pubmed>
  16. <pubmed>12627230</pubmed>
  17. Smith, N. (2008). Characteristics of Kallmann’s syndrome and HH. Retrieved from http://kallmanns.org/node/96.
  18. 18.0 18.1 18.2 18.3 18.4 18.5 <pubmed>16932275</pubmed>
  19. Smith, N. (2008). Euchanoid Pattern [in Kallmann's Syndrome]. Retrieved from http://kallmanns.org/node/86.
  20. <pubmed>1080088</pubmed>
  21. <pubmed>6881209</pubmed>
  22. <pubmed>11531922</pubmed>
  23. <pubmed>11297579</pubmed>
  24. 24.0 24.1 24.2 <pubmed>11052640</pubmed>
  25. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001427/
  26. <pubmed>21543621</pubmed>
  27. <pubmed>21943152</pubmed>
  28. <pubmed>22906231</pubmed>
  29. <pubmed>22912413</pubmed>
  30. 30.0 30.1 30.2 30.3 <pubmed>22416012</pubmed>
  31. 31.0 31.1 <pubmed>22046273</pubmed>
  32. 32.0 32.1 32.2 <pubmed>22581782</pubmed>

External Links

The Neural Basis of Olfaction

Development of the Olfactory System

The Development of the Olfactory System 2

General Physiology of Olfaction

Neural Development


External Links Notice - The dynamic nature of the internet may mean that some of these listed links may no longer function. If the link no longer works search the web with the link text or name. Links to any external commercial sites are provided for information purposes only and should never be considered an endorsement. UNSW Embryology is provided as an educational resource with no clinical information or commercial affiliation.

--Mark Hill 12:22, 15 August 2012 (EST) Please leave the content listed below the line at the bottom of your project page.


2012 Projects: Vision | Somatosensory | Taste | Olfaction | Abnormal Vision | Hearing