Attractant and repellent cues cooperate in guiding a subset of olfactory sensory axons to a well-defined protoglomerular target

Taku, Alemji A.; Marcaccio, Christina L.; Ye, Wenda; Krause, Gregory J.; Raper, Jonathan A.

doi:10.1242/dev.127985

Cited by 14 publications

(18 citation statements)

References 73 publications

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“…By performing in situ hybridization against Sema3A and Slit1 on control and Arx-1 null mice we confirmed that the forebrain is a large source of repellent molecules, which in concert, might prevent the olfactory and vomeronasal fibers, but not the TN nor the GnRH-1ns, from invading the brain (Renzi et al, 2000;Nguyen-Ba-Charvet et al, 2008). As shown previously, we observed that the Sema3 receptors, NRP1 and NRP2, are expressed by olfactory and vomeronasal neurons projecting to different regions of the MOB and AOB (Cloutier et al, 2002;Walz et al, 2002;Cloutier et al, 2004;Taku et al, 2016); however we could only detect NRP1 but not NRP2 immuno-reactivity on GnRH-1ns and TN axons Hanchate et al, 2012;Giacobini and Prevot, 2013;Giacobini, 2015). By performing in situ hybridization against Sema3A in combination with immunofluorescence for GnRH-1 and Peripherin, we observed that the TN and GnRH-1 invade the brain crossing a source of Sema3A.…”

Section: ) Led Us To Question Whether This Link Was Truly Causalsupporting

confidence: 87%

Olfactory and vomeronasal innervation of the olfactory bulbs are not essential for GnRH-1 neuronal migration to the brain

Taroc

Prasad

Lin

et al. 2017

Preprint

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Gonadotropin releasing hormone-1 (GnRH-1) neurons migrate from the developing olfactory pit into the hypothalamus during embryonic development. Migration of the GnRH-1 neurons is required for mammalian reproduction as these cells control release of gonadotropins from the anterior pituitary gland.Disturbances in GnRH-1 cell migration, GnRH-1 synthesis, secretion or signaling lead to varying degrees of hypogonadotropic hypogonadism (HH), which impairs pubertal onset and fertility. HH associated with congenital olfactory defects is clinically defined as Kallmann Syndrome (KS).The association of olfactory defects with HH in KS suggested potential direct relationship between defective olfactory axonal routing, lack of olfactory bulbs and aberrant GnRH-1 cell migration. However, it has never been experimentally proven that the formation of axonal connections of the olfactory and vomeronasal neurons to their functional targets are necessary for the migration GnRH-1 neurons to the hypothalamus.Loss-of-function of the Arx-1 homeobox gene leads to the lack of proper formation of the olfactory bulbs with abnormal axonal termination of olfactory sensory neurons (Yoshihara et al., 2005). We exploited the Arx-1 null mouse line to investigate the role of the olfactory system (olfactory/vomeronasal fibers and OBs) in controlling GnRH-1 migration to the hypothalamus. Our data proves that correct development of the OBs, and axonal connection of the olfactory and vomeronasal sensory neurons to the forebrain are not needed for GnRH-1 neuronal migration. Moreover, we prove that the terminal nerve, which forms the GnRH-1 migratory scaffold, follows different guidance cues and differs in its genetic expression from olfactory and vomeronasal sensory neurons. Significance StatementGonadotropin Releasing Hormone-1 (GnRH-1) neurons control the reproductive axis of vertebrates. During embryonic development, these neurons migrate from the olfactory pit to the hypothalamus. GnRH-1 cell migration is commonly believed to take place along the olfactory axons. Our work reveals that correct olfactory bulb development and targeting of the olfactory and vomeronasal sensory neurons to the brain are not required for this migration. Our work challenges the idea that GnRH-1 neuronal migration to the hypothalamus relies on correct routing of the olfactory and vomeronasal sensory neurons. We provide a new basis for interpreting genetic correlations between anosmia, lack of olfactory bulbs, and hypogonadotropic hypogonadism in Kallmann Syndrome.

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Section: ) Led Us To Question Whether This Link Was Truly Causalsupporting

confidence: 87%

Olfactory and vomeronasal innervation of the olfactory bulbs are not essential for GnRH-1 neuronal migration to the brain

Taroc

Prasad

Lin

et al. 2017

Preprint

View full text Add to dashboard Cite

show abstract

“…By performing ISH against Sema3A and Slit1 on control and Arx-1 null mice we confirmed that the forebrain is a large source of repellent molecules, which, in concert, might prevent the olfactory and vomeronasal fibers, but not the TN nor the GnRH-1 ns, from invading the brain ( Nguyen-Ba-Charvet et al, 2008 ; Renzi et al, 2000 ). We observed that the Sema3 receptors, NRP1 and NRP2, are expressed by olfactory and vomeronasal neurons projecting to different regions of the MOB and AOB ( Cloutier et al, 2002 , 2004 ; Taku et al, 2016 ; Walz et al, 2002 ); however, we could only detect NRP1 but not NRP2 immuno-reactivity on GnRH-1 ns and TN axons ( Cariboni et al, 2011 ; Giacobini, 2015 ; Giacobini and Prevot, 2013 ; Hanchate et al, 2012 ). By performing ISH against Sema3A in combination with immunofluorescence for GnRH-1 and Peripherin, we observed that the TN and GnRH-1 invade the brain crossing a source of Sema3A.…”

Section: Discussionmentioning

confidence: 62%

The terminal nerve plays a prominent role in GnRH-1 neuronal migration independent from proper olfactory and vomeronasal connections to the olfactory bulbs

et al. 2017

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Gonadotropin-releasing hormone-1 (GnRH-1) neurons (GnRH-1 ns) migrate from the developing olfactory pit into the hypothalamus during embryonic development. Migration of the GnRH-1 neurons is required for mammalian reproduction as these cells control release of gonadotropins from the anterior pituitary gland. Disturbances in GnRH-1 ns migration, GnRH-1 synthesis, secretion or signaling lead to varying degrees of hypogonadotropic hypogonadism (HH), which impairs pubertal onset and fertility. HH associated with congenital olfactory defects is clinically defined as Kallmann Syndrome (KS). The association of olfactory defects with HH in KS suggested a potential direct relationship between defective olfactory axonal routing, lack of olfactory bulbs (OBs) and aberrant GnRH-1 ns migration. However, it has never been experimentally proven that the formation of axonal connections of the olfactory/vomeronasal neurons to their functional targets are necessary for the migration of GnRH-1 ns to the hypothalamus. Loss-of-function of the Arx-1 homeobox gene leads to the lack of proper formation of the OBs with abnormal axonal termination of olfactory sensory neurons ( Yoshihara et al., 2005). Our data prove that correct development of the OBs and axonal connection of the olfactory/vomeronasal sensory neurons to the forebrain are not required for GnRH-1 ns migration, and suggest that the terminal nerve, which forms the GnRH-1 migratory scaffold, follows different guidance cues and differs in gene expression from olfactory/vomeronasal sensory neurons.

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“…Whether this difference originates in their differential patterns of expression, or differences in their functional responses to ligands, is unknown. Previous work has shown that CZ projecting axons have an nrp1a -dependent repellent response that is mediated by sema3d expressed anteriorly in the bulb [ 64 ], but many other potential semaphorin ligands are expressed in the bulb and some of them could have additional guidance effects. The ligand(s) that mediate Nrp1b’s contribution to DZ targeting are unknown.…”

Section: Discussionmentioning

confidence: 99%

Coordination of olfactory receptor choice with guidance receptor expression and function in olfactory sensory neurons

et al. 2018

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Olfactory sensory neurons choose to express a single odorant receptor (OR) from a large gene repertoire and extend axons to reproducible, OR-specific locations within the olfactory bulb. This developmental process produces a topographically organized map of odorant experience in the brain. The axon guidance mechanisms that generate this pattern of connectivity, as well as those that coordinate OR choice and axonal guidance receptor expression, are incompletely understood. We applied the powerful approach of single-cell RNA-seq on newly born olfactory sensory neurons (OSNs) in young zebrafish larvae to address these issues. Expression profiles were generated for 56 individual Olfactory Marker Protein (OMP) positive sensory neurons by single-cell (SC) RNA-seq. We show that just as in mouse OSNs, mature zebrafish OSNs typically express a single predominant OR transcript. Our previous work suggests that OSN targeting is related to the OR clade from which a sensory neuron chooses to express its odorant receptor. We categorized each of the mature cells based on the clade of their predominantly expressed OR. Transcripts expressed at higher levels in each of three clade-related categories were identified using Penalized Linear Discriminant Analysis (PLDA). A genome-wide approach was used to identify membrane-associated proteins that are most likely to have guidance-related activity. We found that OSNs that choose to express an OR from a particular clade also express specific subsets of potential axon guidance genes and transcription factors. We validated our identification of candidate axon guidance genes for one clade of OSNs using bulk RNA-seq from a subset of transgene-labeled neurons that project to a single protoglomerulus. The differential expression patterns of selected candidate guidance genes were confirmed using fluorescent in situ hybridization. Most importantly, we observed axonal mistargeting in knockouts of three candidate axonal guidance genes identified in this analysis: nrp1a, nrp1b, and robo2. In each case, targeting errors were detected in the subset of axons that normally express these transcripts at high levels, and not in the axons that express them at low levels. Our findings demonstrate that specific, functional, axonal guidance related genes are expressed in subsets of OSNs that that can be categorized by their patterns of OR expression.

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Attractant and repellent cues cooperate in guiding a subset of olfactory sensory axons to a well-defined protoglomerular target

Cited by 14 publications

References 73 publications

Olfactory and vomeronasal innervation of the olfactory bulbs are not essential for GnRH-1 neuronal migration to the brain

Olfactory and vomeronasal innervation of the olfactory bulbs are not essential for GnRH-1 neuronal migration to the brain

The terminal nerve plays a prominent role in GnRH-1 neuronal migration independent from proper olfactory and vomeronasal connections to the olfactory bulbs

Coordination of olfactory receptor choice with guidance receptor expression and function in olfactory sensory neurons

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