Smad4-dependent morphogenic signals control the maturation and axonal targeting of basal vomeronasal sensory neurons to the accessory olfactory bulb

Abstract

The vomeronasal organ (VNO) contains two main types of vomeronasal sensory neurons (VSNs) that express distinct vomeronasal receptor (VR) genes and localize to specific regions of the neuroepithelium. Morphogenic signals are crucial in defining neuronal identity and network formation; however, if and what signals control maturation and homeostasis of VSNs is largely unexplored. Here, we found transforming growth factor β (TGFβ) and bone morphogenetic protein (BMP) signal transduction in postnatal mice, with BMP signaling being restricted to basal VSNs and at the marginal zones of the VNO: the site of neurogenesis. Using different Smad4 conditional knockout mouse models, we disrupted canonical TGFβ/BMP signaling in either maturing basal VSNs (bVSNs) or all mature VSNs. Smad4 loss of function in immature bVSNs compromises dendritic knob formation, pheromone induced activation, correct glomeruli formation in the accessory olfactory bulb (AOB) and survival. However, Smad4 loss of function in all mature VSNs only compromises correct glomeruli formation in the posterior AOB. Our results indicate that Smad4-mediated signaling drives the functional maturation and connectivity of basal VSNs.

A comprehensive analysis of vomeronasal organ transcriptome reveals variable gene expression depending on age and function in rabbits

“…GO term and KEGG pathway enrichment analyses of the expressed genes (≥ 20 reads) (Supplementary file 2) revealed the over-representation of several remarkable functional categories such as PI3K-Akt signaling, an important pathway for survival and proliferation of vomeronasal sensory neurons (VSNs) (Xia et al 2006); Transforming Growth Factor Beta Receptor, which appears to be involved in the network between the VNO and the accessory olfactory bulb (AOB) (Naik et al 2020); and Wnt signaling, which is involved in olfactory connections and also regulates stem cell fate in the main olfactory epithelium (Zaghetto et al 2007; Fletcher et al 2017).…”

“…The functional maturation and connectivity of basal VSNs in mice is driven by Smad4 through the canonical BMP/TGFβ signaling pathway (Naik et al 2020). We found this gene as the highest expressed one (> 773 reads) among the 8 belonging to Smad family in the rabbit VNO transcriptome.…”

“…Receptor, which appears to be involved in the network between the VNO and the accessory olfactory bulb (AOB) (Naik et al 2020); and Wnt signaling, which is involved in olfactory connections and also regulates stem cell fate in the main olfactory epithelium (Zaghetto et al 2007;Fletcher et al 2017).…”

Mechanisms underlying pre- and postnatal development of the vomeronasal organ

“…a Is based on [159,160]; b is based on [27,64] and c is based on [26,76,121,126] ◂ From E13.5, the VNO increases in size and length, such that a cross-section resembles a kidney shape with a crescent shaped lumen separating the sensory and nonsensory epithelia. Unlike the main olfactory epithelium (MOE), blood vessels and perivascular connective tissue in the vomeronasal sensory epithelium are detectable from embryonic to postnatal life [56,67,68]. The VNO opens anteriorly and connects to the nasal cavity through a narrow vomeronasal duct.…”

“…Fgf8 mutants do not form GnRH-1 neurons and have no vomeronasal neurogenesis. Figure 2 is based on [118,154] [68] sensory epithelium, thus delineating respiratory vs neurogenic domains. The authors also proposed that the effect of Fgf8 inactivation on olfactory and VNO disruption is indirect and due to a broader Bmp4 expression, which expanded into the VNO region preventing neurogenesis (Fig.…”