Sensory - Smell Development

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Human embryo (stage 22) nasal epithelium development.

These notes introduce the development of the sense of smell or olfaction and the associated structures including the nasal placode, olfactory epithelium, olfactory bulb, and vomeronasal organ. Recent research has shown a relationship between what the receptive epithelium is exposed too and how the central neural pathway develops, similar to that shown earlier for the vision system. See also a review on the cell biology of smell.[1]

A French research group has recently been investigating the development of smell in the fetus and in neonates. The nasal epithelium has also been a research "hot topic" as it is one of the few easily accessible sites of adult neural stem cells.

Note the different spellings "odour" (UK) or "odor" (USA). Anosmia is the term used to describe having no sense of smell. Anosmia/hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts.

Smell Links: Introduction | placode | Rhinencephalon | head | respiratory | Student project | taste | sensory | Category:Smell
Historic Smell 
Historic Embryology: 1902 Olfactory Structures | 1910 cavum nasi | 1940 Olfactory and Accessory Olfactory Formations | 1941 Olfactory nerve | 1980 Staged embryos

Senses Links: Introduction | placode | Hearing and Balance hearing | balance | vision | smell | taste | touch | Stage 22 | Category:Sensory

Some Recent Findings

  • Common olfactory ensheathing glial markers in the developing human olfactory system[2] "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."
More recent papers  
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Search term: Olfactory Development | Smell Development | Smell Embryology | nasal placode | olfactory epithelium | olfactory bulb | vomeronasal organ | anosmia

Older papers  
These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table.

See also the Discussion Page for other references listed by year and References on this current page.

  • The perceptual logic of smell[3] "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.
  • The dual origin of the peripheral olfactory system: placode and neural crest[4] "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. ...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."
  • Loss-of-function mutations in sodium channel Nav1.7 cause anosmia.[5] "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."
  • The cell biology of smell[1] "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."
  • Maturation of the olfactory sensory neurons by Apaf-1/caspase-9-mediated caspase activity[6] "Although the apoptotic role of caspases has been largely understood, accumulating evidence in Drosophila suggests that caspases also control other processes than apoptotic cell death. However, how caspases contribute to the development of the mammalian nervous system remains obscure. Here, we provide unique evidence that Apaf-1/caspase-9-mediated caspase signaling regulates the development of olfactory sensory neurons (OSNs), which includes axonal projection, synapse formation, and maturation of these neurons."

Nasal Placode


The olfactory epithelium develops from the paired nasal placodes, each develop initially with two components, a medial and lateral region.

Carnegie stage 13

Stage 13 image 063.jpg

Carnegie stage 13 - serial sections nasal placode sections
Stage 13 image 059.jpg Stage 13 image 060.jpg Stage 13 image 061.jpg Stage 13 image 062.jpg
Stage 13 image 063.jpg Stage 13 image 064.jpg Stage 13 image 065.jpg Stage 13 image 066.jpg
Nasal Placode - Human Embryo stage 14
Stage14 sem2b-limb.jpg

In the mouse, gonadotropin-releasing hormone-1 neurones control the release of gonadotropins from the anterior pituitary and were thought to originate from the adenohypophyseal placed. A recent study has shown that the real origin is associated with the formation of the nasal placode.[7]

Links: placode | Search PubMed

Olfactory Epithelium

Adult - pseudostratified columnar epithelium overlying a lamina propria

Five basic cell types:

  1. horizonatal basal cells - not present embryonically.
  2. globose basal cells - transit amplifying progenitors of the olfactory epithelium.
  3. sustentacular cells - aligned on the surface with thin cytoplasmic projections terminating at the basal lamina.
  4. olfactory receptor neurons - located in an intermediate zone between basal and apical layers, form the bulk of the epithelium.
  5. olfactory gland cells (Bowman's gland/duct complex) - extend from the glands in the lamina propria to the ducts within the epithelium. Function to carry secretions to the apical epithelial surface.

Olfactory Ensheathing Cells

  • neural crest in origin.[4]
  • accompany and ensheath the small olfactory axons of the nonmyelinated olfactory nerves.
  • compartmentalize the small olfactory axons into fascicles.
  • allow regenerating olfactory nerves to cross the peripheral/central nerve threshold.
Links: neural crest

Olfactory Receptors

Odours bind to and activate olfactory receptors located on the dendrites of sensory neurons in the nose and how the mitral cells of the olfactory bulb (OB) process olfactory information. What has yet to be thoroughly described is how the piriform cortex receives and transforms information arriving from the OB via the lateral olfactory tract (LOT). Although the cell types present in the piriform cortex are known (Shepherd, 2004), previous work has failed to differentiate between disparate electrophysiological profiles and synaptic contacts made between principal cells.


Embryonic Smell Development
Week FA (GA) Carnegie Stage Event
week 4 (GA 6) 11 nasal epiblastic thickening appears
12 nasal field is well outlined
week 5 (GA 7) 15 continuous cellulovascular strand seen between the nasal groove and the olfactory field
week 6 (GA 8) 16 vomeronasal groove appears.
17 olfactory nerve is organized into two plexuses, lateral and medial, the latter mingled with the terminal-vomeronasal complex.
week 7 (GA 9) 18 olfactory bulb begins to appear
19 individualization of the olfactory bulb and nuclei, distinction between olfactory structures and terminal and vomeronasal ones begins to be clear.
week 8 (GA 10) 21 structure of the olfactory bulb is evident.
23 olfactory strands are well individualized, and olfactory and terminal-vomeronasal fibers are easily distinguishable.
Links: smell | sensory | timeline | Category:Timeline    Table Data Reference[8]

Week 5 to 8 - Stage 15, 17, 20

Human embryo olfactory 01.jpg

Development of the Human Olfactory System (Carnegie Stage 15, 17 and 20)[9]

Abbreviations: (cal) calretinin immunostaining, (CS) Carnegie stage, (HE) hematoxylin-eosin staining, (MZ) marginal zone, (OB) olfactory bulb, (OP) olfactory placode, (Tel) telencephalon.

Week 8 - Stage 22

Nasal epithelium development (stage 22)

Stage 22 image 209.jpg

Olfactory Pathway

Olfactory receptor neurons (ORNs) - odours bind and activate olfactory receptors located on dendrites of sensory neurons in the nose.

Olfactory bulb (OB) - Mitral cells process olfactory information (encoded in a chemotopic map).

Lateral olfactory tract (LOT) - pathway to cortex.

Primary olfactory cortex (= Piriform cortex) - receives and transforms information.

Mouse-olfactory nerve pathway development.jpg

Mouse olfactory nerve pathway development[10]

Vomeronasal Accessory Olfactory System

Stage 22 vomeronasal organ.jpg Human Embryo (week 8, Carnegie stage 22)

Transverse section through the embryo head nasal region showing the developing Vomeronasal Organ (VNO) or Jacobson's organ. This contains sensory neurons that detect chemical stimuli (pheromones)

Accessory olfactory system

  1. VNO axons project to the accessory olfactory bulb,
  2. amygdala and bed nucleus of the stria terminalis
  3. project to the hypothalamus.
Mouse-solitary chemosensory cells.jpg Adult Mouse VMO anatomical position and showing also solitary chemosensory cells[11]

The vomeronasal accessory olfactory system (vomeronasal organ, VNO) is involved in detecting and transfering pheromone information through the vomeronasal nerve (nervus vomeronasalis) to the neuroendocrine hypothalamus. This signaling pathway can be used for mating and as olfactory cues for nocturnal animals. There are two families of receptors located in the vomeronasal organ the V1Rs and the V2Rs, are thought to detect pheromonal signals.[12]

Human embryos also have a vomeronasal organ, though later many structures such as the vomeronasal nerve, accessory olfactory bulb and chemoreceptor cells within the organ are lost. Therefore it is not clear whether there is any postnatal neuroendocrine role for this structure.[13][14]

Grueneberg Ganglion

The Grueneberg (Grüneberg) ganglion[15] "Within the nasal epithelium of mammals, there are several compartments which are populated with neuronal cells. One of them - the so-called Grueneberg ganglion - is composed of ciliated neurons residing in the anterior region of the nose."

Identified mainly in rodents, first identified in 1973 by Hans Grüneberg.


Olfactory Region overview | Olfactory Region Epithelium

Links: Olfactory Region overview | Olfactory Region Epithelium | Respiratory Histology

Animal Models


The nasal mucosa features four separate olfactory areas:

  1. main olfactory epithelium (MOE)
  2. septal organ (SO)
  3. ganglion of Grüneberg (GG)
  4. vomeronasal sensory epithelium (VNsE) forms a part of the vomeronasal organ (VNO)
Links: mouse


Retinoid acid

Retinoid acid model in olfactory development.jpg

Retinoic acid model in olfactory development[16]

Links: retinoic acid



Term used to describe having no sense of smell. Anosmia/hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts.

Kallmann Syndrome

  • A developmental disease affecting both the hormonal reproductive axis and the sense of smell.
  • Affected individuals have mutations in either of two different genes KAL1 and FGFR1 (20%) and prokineticin receptor-2 (PROKR2) or prokineticin-2 (PROK2) genes (10%).

Links: GeneReviews - Kallmann Syndrome | Genetics Home Reference

Choanal Atresia

[[File:Choanal atresia computed tomography 01.jpg|thumb|Choanal atresia computed tomography[17]

  • Choanal atresia is the most common form of congenital nasal obstruction, usually diagnosed at birth.[17]
  • failure of the posterior nasal cavity (choanae) to communicate with the nasopharynx.
  • unilateral or bilateral bony membranous septum located between the nose and the pharynx.
  • occurs in approximately 1 in 5000 to 7000 live births.
  • Thought to be secondary to an abnormality during the rupture of the buccopharyngeal membrane in the embryological period.

Additional Images


Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.


  1. 1.0 1.1 DeMaria S & Ngai J. (2010). The cell biology of smell. J. Cell Biol. , 191, 443-52. PMID: 21041441 DOI.
  2. Oprych K, Cotfas D & Choi D. (2017). Common olfactory ensheathing glial markers in the developing human olfactory system. Brain Struct Funct , 222, 1877-1895. PMID: 27718014 DOI.
  3. Secundo L, Snitz K & Sobel N. (2014). The perceptual logic of smell. Curr. Opin. Neurobiol. , 25, 107-15. PMID: 24440370 DOI.
  4. 4.0 4.1 Katoh H, Shibata S, Fukuda K, Sato M, Satoh E, Nagoshi N, Minematsu T, Matsuzaki Y, Akazawa C, Toyama Y, Nakamura M & Okano H. (2011). The dual origin of the peripheral olfactory system: placode and neural crest. Mol Brain , 4, 34. PMID: 21943152 DOI.
  5. 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. (2011). Loss-of-function mutations in sodium channel Nav1.7 cause anosmia. Nature , 472, 186-90. PMID: 21441906 DOI.
  6. Ohsawa S, Hamada S, Kuida K, Yoshida H, Igaki T & Miura M. (2010). Maturation of the olfactory sensory neurons by Apaf-1/caspase-9-mediated caspase activity. Proc. Natl. Acad. Sci. U.S.A. , 107, 13366-71. PMID: 20624980 DOI.
  7. Metz H & Wray S. (2010). Use of mutant mouse lines to investigate origin of gonadotropin-releasing hormone-1 neurons: lineage independent of the adenohypophysis. Endocrinology , 151, 766-73. PMID: 20008041 DOI.
  8. Bossy J. Development of olfactory and related structures in staged human embryos. (1980) Anat. Embryol., 161(2);225-36 PMID 7469043
  9. Antal MC, Samama B, Ghandour MS & Boehm N. (2015). Human Neural Cells Transiently Express Reelin during Olfactory Placode Development. PLoS ONE , 10, e0135710. PMID: 26270645 DOI.
  10. Miller AM, Maurer LR, Zou DJ, Firestein S & Greer CA. (2010). Axon fasciculation in the developing olfactory nerve. Neural Dev , 5, 20. PMID: 20723208 DOI.
  11. Ogura T, Krosnowski K, Zhang L, Bekkerman M & Lin W. (2010). Chemoreception regulates chemical access to mouse vomeronasal organ: role of solitary chemosensory cells. PLoS ONE , 5, e11924. PMID: 20689832 DOI.
  12. Karn RC, Young JM & Laukaitis CM. (2010). A candidate subspecies discrimination system involving a vomeronasal receptor gene with different alleles fixed in M. m. domesticus and M. m. musculus. PLoS ONE , 5, . PMID: 20844586 DOI.
  13. Witt M & Hummel T. (2006). Vomeronasal versus olfactory epithelium: is there a cellular basis for human vomeronasal perception?. Int. Rev. Cytol. , 248, 209-59. PMID: 16487792 DOI.
  14. Dénes L, Pap Z, Szántó A, Gergely I & Pop TS. (2015). Human vomeronasal epithelium development: An immunohistochemical overview. Acta Microbiol Immunol Hung , 62, 167-81. PMID: 26132837 DOI.
  15. Fleischer J & Breer H. (2010). The Grueneberg ganglion: a novel sensory system in the nose. Histol. Histopathol. , 25, 909-15. PMID: 20503179 DOI.
  16. Paschaki M, Cammas L, Muta Y, Matsuoka Y, Mak SS, Rataj-Baniowska M, Fraulob V, Dollé P & Ladher RK. (2013). Retinoic acid regulates olfactory progenitor cell fate and differentiation. Neural Dev , 8, 13. PMID: 23829703 DOI.
  17. 17.0 17.1 Al-Noury K & Lotfy A. (2011). Role of multislice computed tomography and local contrast in the diagnosis and characterization of choanal atresia. Int J Pediatr , 2011, 280763. PMID: 21772853 DOI.


Sarnat HB & Flores-Sarnat L. (2017). Olfactory Development, Part 2: Neuroanatomic Maturation and Dysgeneses. J. Child Neurol. , 32, 579-593. PMID: 28424008 DOI.

Sarnat HB, Flores-Sarnat L & Wei XC. (2017). Olfactory Development, Part 1: Function, From Fetal Perception to Adult Wine-Tasting. J. Child Neurol. , 32, 566-578. PMID: 28424010 DOI.

DeMaria S & Ngai J. (2010). The cell biology of smell. J. Cell Biol. , 191, 443-52. PMID: 21041441 DOI.

Gane S. (2010). What we do not know about olfaction. Part 1: from nostril to receptor. Rhinology , 48, 131-8. PMID: 20502748 DOI.

Yuan TF. (2010). Smell with new neurons. Cell Tissue Res. , 340, 211-4. PMID: 20387075 DOI.

Schoppa NE. (2009). Making scents out of how olfactory neurons are ordered in space. Nat. Neurosci. , 12, 103-4. PMID: 19172161 DOI.

Munger SD, Leinders-Zufall T & Zufall F. (2009). Subsystem organization of the mammalian sense of smell. Annu. Rev. Physiol. , 71, 115-40. PMID: 18808328 DOI.

Wilson RI. (2008). Neural and behavioral mechanisms of olfactory perception. Curr. Opin. Neurobiol. , 18, 408-12. PMID: 18809492 DOI.


Dénes L, Pap Z, Szántó A, Gergely I & Pop TS. (2015). Human vomeronasal epithelium development: An immunohistochemical overview. Acta Microbiol Immunol Hung , 62, 167-81. PMID: 26132837 DOI.

Bossy J. (1980). Development of olfactory and related structures in staged human embryos. Anat. Embryol. , 161, 225-36. PMID: 7469043

Search PubMed

Search Pubmed: Smell Development | olfactory receptors | Olfactory bulb development | anosmia


Humphrey T. The development of the olfactory and the accessory olfactory formations in human embryos and fetuses. (1940) J. Comp. Neurol. 431-468.

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  • glomerulus - the functional unit of the olfactory bulb.
  • odorant - a compound that elicits the perception of smell.
  • odorant receptor - (OR) a receptor expressed by an olfactory sensory neuron. Receptor belongs to the G protein–coupled receptors (GPCR) superfamily. There are multiple families of odorant receptors, which include the OR (the largest family), TAAR, V1R, V2R, and formyl peptide-like receptors.
  • olfactory cortex - refers to the brain regions that receive direct input from the olfactory bulb are responsible for the perception of smell and for generating odor-evoked behaviours. The five brain regions are the: piriform cortex, anterior olfactory nucleus, olfactory tubercle, entorhinal cortex, and amygdala.
  • olfactory glomeruli - spherically shaped regions of neuropil where information is passed from sensory neurons to postsynaptic neurons.
  • vomeronasal organ (VNO, Jacobson's organ) A neural structure forming part of olfactory system that functions in the detection of pheromones. In humans, the vomeronasal nerve, accessory olfactory bulb and chemoreceptor cells within the organ are lost. Named after Ludwig Lewin Jacobson (1783 – 1843) a Danish surgeon who identified it in 1813.

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