RGMB and neogenin control cell differentiation in the developing olfactory epithelium

Abstract

Cellular interactions are key for the differentiation of distinct cell types within developing epithelia, yet the molecular mechanisms engaged in these interactions remain poorly understood. In the developing olfactory epithelium (OE), neural stem/progenitor cells give rise to odorant-detecting olfactory receptor neurons (ORNs) and glial-like sustentacular (SUS) cells. Here, we show in mice that the transmembrane receptor neogenin (NEO1) and its membranebound ligand RGMB control the balance of neurons and glial cells produced in the OE. In this layered epithelium, neogenin is expressed in progenitor cells, while RGMB is restricted to adjacent newly born ORNs. Ablation of Rgmb via gene-targeting increases the number of dividing progenitor cells in the OE and leads to supernumerary SUS cells. Neogenin loss-of-function phenocopies these effects observed in Rgmb −/− mice, supporting the proposal that RGMB-neogenin signaling regulates progenitor cell numbers and SUS cell production. Interestingly, Neo1−/− mice also exhibit increased apoptosis of ORNs, implicating additional ligands in the neogenin-dependent survival of ORNs. Thus, our results indicate that RGMB-neogenin-mediated cellcell interactions between newly born neurons and progenitor cells control the ratio of glia and neurons produced in the OE.

Diverse spinal commissural neuron populations revealed by fate mapping and molecular profiling using a novel Robo3Cre mouse

“…Chl1 encodes a member of the L1 family of adhesion molecules that is involved in neurite outgrowth (Hillenbrand, Montag, & Schachner, ; Montag‐Sallaz, Schachner, & Montag, ), and Thsd7a encodes a thrombospondin repeat‐rich protein involved in angiogenesis (Wang et al, ). The protein encoded by Dner (Delta/Notch‐like EGF‐related receptor) has been implicated in neuronal proliferation, differentiation, and neuritogenesis (Du, Wang, Zhang, Zhang, & Jiang, ; Eiraku, Hirata, Takeshima, Hirano, & Kengaku, ; Hsieh et al, ), and Rgmb encodes a glycosylphosphatidylinositol‐anchored repulsive guidance molecule family member which regulates cell differentiation and nervous system patterning (Kam et al, ; Samad et al, ). Sst , Kif26b , Mab21l2 , and Lamp5 mRNAs are also highly enriched and expressed in C‐neurons (Figure h).…”

Distinct functions for netrin 1 in chicken and murine semicircular canal morphogenesis

“…However, fusion proceeds normally in all mouse mutants that have been examined so far (Abraira et al, 2008;Matilainen et al, 2007), including Dcc; Neo1 double mutants (Fig. S2), which carry a null allele of Dcc and a severely hypomorphic allele of Neo1 (Fazeli et al, 1997;Kam et al, 2016). Chickens do not seem to have a Dcc gene (Friocourt et al, 2017) and instead rely solely on Neo1, at least for axon guidance (Phan et al, 2011).…”

Neogenin Recruitment of the WAVE Regulatory Complex to Ependymal and Radial Progenitor Adherens Junctions Prevents Hydrocephalus

“…Neogenin is an axon guidance receptor for both Netrin-1 and the repulsive guidance molecules (RGMs) and also regulates neurogenesis, neuronal migration, and neural regeneration (Kam et al, 2016;O'Leary et al, 2013O'Leary et al, , 2015Rajagopalan et al, 2004;Siebold et al, 2017;van Erp et al, 2015). In the early neural tube, Neogenin is required for the establishment of neuroepithelial adhesion and apicobasal polarity (Kee et al, 2008(Kee et al, , 2013Mawdsley et al, 2004).…”