Talk:Sensory - Smell Development

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Cite this page: Hill, M.A. (2021, December 4) Embryology Sensory - Smell Development. Retrieved from


Common olfactory ensheathing glial markers in the developing human olfactory system

Brain Struct Funct. 2017 May;222(4):1877-1895. doi: 10.1007/s00429-016-1313-y. Epub 2016 Oct 7.

Oprych K1, Cotfas D2, Choi D2,3.


The in situ immunocytochemical properties of olfactory ensheathing cells (OECs) have been well studied in several small to medium sized animal models including rats, mice, guinea pigs, cats and canines. However, we know very little about the antigenic characteristics of OECs in situ within the adult and developing human olfactory bulb and nerve roots. To address this gap in knowledge we undertook an immunocytochemical analysis of the 11-19 pcw human foetal olfactory system. Human foetal OECs in situ possessed important differences compared to rodents in the expression of key surface markers. P75NTR was not observed in OECs but was strongly expressed by human foetal Schwann cells and perineurial olfactory nerve fibroblasts surrounding OECs. We define OECs throughout the 11-19 pcw human olfactory system as S100/vimentin/SOX10+ with low expression of GFAP. Our results suggest that P75NTR is a robust marker that could be utilised with cell sorting techniques to generate enriched OEC cultures by first removing P75NTR expressing Schwann cells and fibroblasts, and subsequently to isolate OECs after P75NTR upregulation in vitro. O4 and PSA-NCAM were not found to be suitable surface antigens for OEC purification owing to their ambiguous and heterogeneous expression. Our results highlight the importance of corroborating cell markers when translating cell therapies from animal models to the clinic. KEYWORDS: Foetal; Human; Immunocytochemistry; OEC; Olfactory bulb; Olfactory ensheathing cells PMID: 27718014 PMCID: PMC5406434 DOI: 10.1007/s00429-016-1313-y [Indexed for MEDLINE] Free PMC Article

Olfactory Development, Part 1: Function, From Fetal Perception to Adult Wine-Tasting

J Child Neurol. 2017 May;32(6):566-578. doi: 10.1177/0883073817690867. Epub 2017 Feb 19.

Sarnat HB1,2,3,4, Flores-Sarnat L1,2,3,4, Wei XC5,4.


Discrimination of odorous molecules in amniotic fluid occur after 30 weeks' gestation; fetuses exhibit differential responses to maternal diet. Olfactory reflexes enable reliable neonatal testing. Olfactory bulbs can be demonstrated reliably by MRI after 30 weeks' gestation, and their hypoplasia or aplasia also documented by late prenatal and postnatal MRI. Olfactory axons project from nasal epithelium to telencephalon before olfactory bulbs form. Fetal olfactory maturation remains incomplete at term for neuronal differentiation, synaptogenesis, myelination, and persistence of the transitory fetal ventricular recess. Immaturity does not signify nonfunction. Olfaction is the only sensory system without thalamic projection because of its own intrinsic thalamic equivalent. Diverse malformations of the olfactory bulb can be diagnosed by clinical examination, imaging, and neuropathology. Some epileptic auras might be primarily generated in the olfactory bulb. Cranial nerve 1 should be tested in all neonates and especially in patients with brain malformations, endocrinopathies, chromosomopathies, and genetic/metabolic diseases. KEYWORDS: fetal odor perception; olfactory development; olfactory thalamus; progenitors PMID: 28424010 DOI: 10.1177/0883073817690867

Olfactory Development, Part 2: Neuroanatomic Maturation and Dysgeneses

J Child Neurol. 2017 May;32(6):579-593. doi: 10.1177/0883073816685192. Epub 2017 Feb 19.

Sarnat HB1,2,3, Flores-Sarnat L1,3.


Olfactory axons project from nasal epithelium to the primitive telencephalon before olfactory bulbs form. Olfactory bulb neurons do not differentiate in situ but arrive via the rostral migratory stream. Synaptic glomeruli and concentric laminar architecture are unlike other cortices. Fetal olfactory maturation of neuronal differentiation, synaptogenesis, and myelination remains incomplete at term and have a protracted course of postnatal development. The olfactory ventricular recess involutes postnatally but dilates in congenital hydrocephalus. Olfactory bulb, tract and epithelium are repositories of progenitor stem cells in fetal and adult life. Diverse malformations of the olfactory bulb can be diagnosed by clinical examination, imaging, and neuropathologically. Cellular markers of neuronal differentiation and synaptogenesis demonstrate immaturity of the olfactory system at birth, previously believed by histology alone to occur early in fetal life. Immaturity does not preclude function. KEYWORDS: agenesis; bulb; development; dysgenesis; maturation; olfactory epithelium; progenitors; synaptic glomeruli; tract PMID: 28424008 DOI: 10.1177/0883073816685192


Human Neural Cells Transiently Express Reelin during Olfactory Placode Development

PLoS One. 2015 Aug 13;10(8):e0135710. doi: 10.1371/journal.pone.0135710. eCollection 2015.

Antal MC1, Samama B2, Ghandour MS3, Boehm N2.


Reelin, an extracellular glycoprotein is essential for migration and correct positioning of neurons during development. Since the olfactory system is known as a source of various migrating neuronal cells, we studied Reelin expression in the two chemosensory olfactory systems, main and accessory, during early developmental stages of human foetuses/embryos from Carnegie Stage (CS) 15 to gestational week (GW) 14. From CS 15 to CS 18, but not at later stages, a transient expression of Reelin was detected first in the presumptive olfactory and then in the presumptive vomeronasal epithelium. During the same period, Reelin-positive cells detach from the olfactory/vomeronasal epithelium and migrate through the mesenchyme beneath the telencephalon. Dab 1, an adaptor protein of the Reelin pathway, was simultaneously expressed in the migratory mass from CS16 to CS17 and, at later stages, in the presumptive olfactory ensheathing cells. Possible involvements of Reelin and Dab 1 in the peripheral migrating stream are discussed.

PMID 26270645


The perceptual logic of smell

Curr Opin Neurobiol. 2014 Jan 14;25C:107-115. doi: 10.1016/j.conb.2013.12.010. [Epub ahead of print]

Secundo L1, Snitz K1, Sobel N2. Author information


Mammals have ∼1000 different olfactory receptor subtypes, each responding to a number of different odorants, and each odorant activating a number of different receptor subtypes. These molecular and anatomical underpinnings of olfaction imply a perceptual structure of very high dimensionality that relies on combinatorial coding. In contrast to this expectation, the study of olfactory perception reveals a structure of much lower dimensionality. Moreover, a low-dimensionality approach to olfaction enabled derivation of perception-based structural metrics for smell. These metrics provided meaningful predictions of odorant-induced neural activity and perception from odorant structure alone. Based on this low functional dimensionality, we speculate that olfaction likely does not functionally rely on 1000 different receptor subtypes, and their persistence in evolution may imply that they have additional roles in non-olfactory functions such as in guidance of embryogenesis and development. Copyright © 2013 Elsevier Ltd. All rights reserved.

PMID 24440370


Non-redundant coding of aversive odours in the main olfactory pathway

Nature. 2013 May 23;497(7450):486-9. doi: 10.1038/nature12114. Epub 2013 Apr 28.

Dewan A1, Pacifico R, Zhan R, Rinberg D, Bozza T. Author information


Many species are critically dependent on olfaction for survival. In the main olfactory system of mammals, odours are detected by sensory neurons that express a large repertoire of canonical odorant receptors and a much smaller repertoire of trace amine-associated receptors (TAARs). Odours are encoded in a combinatorial fashion across glomeruli in the main olfactory bulb, with each glomerulus corresponding to a specific receptor. The degree to which individual receptor genes contribute to odour perception is unclear. Here we show that genetic deletion of the olfactory Taar gene family, or even a single Taar gene (Taar4), eliminates the aversion that mice display to low concentrations of volatile amines and to the odour of predator urine. Our findings identify a role for the TAARs in olfaction, namely, in the high-sensitivity detection of innately aversive odours. In addition, our data reveal that aversive amines are represented in a non-redundant fashion, and that individual main olfactory receptor genes can contribute substantially to odour perception. Comment in Sensory systems: Encoding aversion. [Nat Rev Neurosci. 2013]

PMID 23624375


Close association of olfactory placode precursors and cranial neural crest cells does not predestine cell mixing

Delopmental Dynamics

Maegan V. Harden1, Luisa Pereiro2, Mirana Ramialison3,†, Jochen Wittbrodt3, Megana K. Prasad4, Andrew S. McCallion4, Kathleen E. Whitlock2,‡,*

Vertebrate sensory organs originate from both cranial neural crest cells (CNCCs) and placodes. Previously we have shown that the olfactory placode (OP) forms from a large field of cells extending caudally to the pre-migratory neural crest domain, and that OPs form through cell movements and not cell division. Concurrent with OP formation CNCCs migrate rostrally to populate the frontal mass. However, little is known about the interactions between CNCCs and the placodes that form the olfactory sensory system. Previous reports suggest that the OP can generate cell types more typical of neural crest lineages such as neuroendocrine cells and glia, thus marking the OP as an unusual sensory placode. One possible explanation for this exception is that the neural crest origin of glia and neurons has been overlooked due to the intimate associated of these two fields during migration. Using molecular markers and live imaging, we followed the development of OP precursors and of dorsally migrating CNCCs in zebrafish embryos. We generated a six4b:mCherry line (OP precursors) that, with a sox10:EGFP line (CNCCs), was used to follow cell migration. Our analyses showed that CNCCs associate with and eventually surround the forming OP with limited cell mixing occurring during this process.;jsessionid=0CBAF650CB4A7BDEB726B708B4AA45EB.d04t01


The dual origin of the peripheral olfactory system: placode and neural crest

Mol Brain. 2011 Sep 23;4:34. Katoh H, Shibata S, Fukuda K, Sato M, Satoh E, Nagoshi N, Minematsu T, Matsuzaki Y, Akazawa C, Toyama Y, Nakamura M, Okano H. Source Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan. Abstract BACKGROUND: The olfactory epithelium (OE) has a unique capacity for continuous neurogenesis, extending axons to the olfactory bulb with the assistance of olfactory ensheathing cells (OECs). The OE and OECs have been believed to develop solely from the olfactory placode, while the neural crest (NC) cells have been believed to contribute only the underlying structural elements of the olfactory system. In order to further elucidate the role of NC cells in olfactory development, we examined the olfactory system in the transgenic mice Wnt1-Cre/Floxed-EGFP and P0-Cre/Floxed-EGFP, in which migrating NC cells and its descendents permanently express GFP, and conducted transposon-mediated cell lineage tracing studies in chick embryos. RESULTS: Examination of these transgenic mice revealed GFP-positive cells in the OE, demonstrating that NC-derived cells give rise to OE cells with morphologic and antigenic properties identical to placode-derived cells. OECs were also positive for GFP, confirming their NC origin. Cell lineage tracing studies performed in chick embryos confirmed the migration of NC cells into the OE. Furthermore, spheres cultured from the dissociated cells of the olfactory mucosa demonstrated self-renewal and trilineage differentiation capacities (neurons, glial cells, and myofibroblasts), demonstrating the presence of NC progenitors in the olfactory mucosa. CONCLUSION: Our data demonstrates that the NC plays a larger role in the development of the olfactory system than previously believed, and suggests that NC-derived cells may in part be responsible for the remarkable capacity of the OE for neurogenesis and regeneration.

PMID 21943152

Loss-of-function mutations in sodium channel Nav1.7 cause anosmia

Nature. 2011 Apr 14;472(7342):186-90. Epub 2011 Mar 23.

Weiss J, Pyrski M, Jacobi E, Bufe B, Willnecker V, Schick B, Zizzari P, Gossage SJ, Greer CA, Leinders-Zufall T, Woods CG, Wood JN, Zufall F. Source Department of Physiology, University of Saarland School of Medicine, 66421 Homburg, Germany.

Abstract Loss of function of the gene SCN9A, encoding the voltage-gated sodium channel Na(v)1.7, causes a congenital inability to experience pain in humans. Here we show that Na(v)1.7 is not only necessary for pain sensation but is also an essential requirement for odour perception in both mice and humans. We examined human patients with loss-of-function mutations in SCN9A and show that they are unable to sense odours. To establish the essential role of Na(v)1.7 in odour perception, we generated conditional null mice in which Na(v)1.7 was removed from all olfactory sensory neurons. In the absence of Na(v)1.7, these neurons still produce odour-evoked action potentials but fail to initiate synaptic signalling from their axon terminals at the first synapse in the olfactory system. The mutant mice no longer display vital, odour-guided behaviours such as innate odour recognition and avoidance, short-term odour learning, and maternal pup retrieval. Our study creates a mouse model of congenital general anosmia and provides new strategies to explore the genetic basis of the human sense of smell. Comment in Nature. 2011 Apr 14;472(7342):173-4.

PMID 21441906


The cell biology of smell

J Cell Biol. 2010 Nov 1;191(3):443-52.

DeMaria S, Ngai J.

Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA 94720, USA. Abstract The olfactory system detects and discriminates myriad chemical structures across a wide range of concentrations. To meet this task, the system utilizes a large family of G protein-coupled receptors-the odorant receptors-which are the chemical sensors underlying the perception of smell. Interestingly, the odorant receptors are also involved in a number of developmental decisions, including the regulation of their own expression and the patterning of the olfactory sensory neurons' synaptic connections in the brain. This review will focus on the diverse roles of the odorant receptor in the function and development of the olfactory system.

PMID: 21041441

Anosmia Predicts Hypogonadotropic Hypogonadism in CHARGE Syndrome

Bergman JE, Bocca G, Hoefsloot LH, Meiners LC, van Ravenswaaij-Arts CM. J Pediatr. 2010 Sep 29.

OBJECTIVE: To test the hypothesis that a smell test could predict the occurrence of hypogonadotropic hypogonadism (HH) in patients with CHARGE syndrome, which is a variable combination of ocular coloboma, heart defects, choanal atresia, retardation of growth/development, genital hypoplasia, and ear anomalies or hearing loss caused by mutations in the CHD7 (chromodomain helicase DNA binding protein 7) gene.

STUDY DESIGN: We performed endocrine studies and smell testing (University of Pennsylvania Smell Identification Test) in 35 adolescent patients with molecularly confirmed CHARGE syndrome.

RESULTS: Complete data on smell and puberty were available for 15 patients; 11 patients had both anosmia and HH, whereas 4 patients had normosmia/hyposmia and spontaneous puberty. In addition, 7 boys were highly suspected of having HH (they were too young for definite HH diagnosis, but all had cryptorchidism, micropenis, or both) and had anosmia. The type of CHD7 mutation could not predict HH because a father and daughter with the same CHD7 mutation were discordant for HH and anosmia.

CONCLUSION: Anosmia and HH were highly correlated in our cohort, and therefore smell testing seems to be an attractive method for predicting the occurrence of HH in patients with CHARGE syndrome. The use of this test could prevent delay of hormonal pubertal induction, resulting in an age-appropriate puberty.

PMID: 20884005


Development of olfactory and related structures in staged human embryos

Anat Embryol (Berl). 1980;161(2):225-36.

Bossy J.


The staged sequence of development of the olfactory and related structures has been established from the serially sectioned human embryos of the Carnegie collection, from stage 11 to stage 23. The nasal epiblastic thickening appears at stage 11 and the nasal field is well outlined at stage 12. At stage 15, a continuous cellulovascular strand is observed between the nasal groove and the olfactory field. The vomeronasal groove appears at stage 16 (O'Rahilly 1967). During stage 17, the olfactory nerve is organized into two plexuses, lateral and medial, the latter mingled with the terminal-vomeronasal complex. The olfactory bulb begins to appear at stage 18. Stage 19 is characterized by the individualization of the olfactory bulb and nuclei. In addition, the distinction between olfactory structures and terminal and vomeronasal ones begins to be clear. The structure of the olfactory bulb is evident at stage 21. At stage 23, the olfactory strands are well individualized, and olfactory and terminal-vomeronasal fibers are easily distinguishable. The terminal ganglion is rather terminal-vomeronasal with an autonomic terminal contingent and a sensory one attached to the vomeronasal system.

PMID 7469043