Abstract
The embryonic olfactory epithelium (OE) generates only a very few olfactory sensory neurons when the basic helix-loop-helix transcription factor, ASCL1 (previously known as MASH1) is eliminated by gene mutation. We have closely examined the structure and composition of the OE of knockout mice and found that the absence of neurons dramatically affects the differentiation of multiple other epithelial cell types as well. The most prominent effect is observed within the two known populations of stem and progenitor cells of the epithelium. The emergence of horizontal basal cells, a multipotent progenitor population in the adult epithelium, is anomalous in the Ascl1 knockout mice. The differentiation of globose basal cells, another multipotent progenitor population in the adult OE, is also aberrant. All of the persisting globose basal cells are marked by SOX2 expression, suggesting a prominent role for SOX2 in progenitors upstream of Ascl1. However, NOTCH1-expressing basal cells are absent from the knockout; since NOTCH1 signaling normally acts to suppress Ascl1 via HES1 and drives sustentacular (Sus) cell differentiation during adult epithelial regeneration, its absence suggests reciprocity between neurogenesis and the differentiation of Sus cells. Indeed, the Sus cells of the mutant mice express a markedly lower level of HES1, strengthening that notion of reciprocity. Duct/gland development appears normal. Finally, the expression of cKIT by basal cells is also undetectable, except in those small patches where neurogenesis escapes the effects of Ascl1 knockout and neurons are born. Thus, persistent neurogenic failure distorts the differentiation of multiple other cell types in the olfactory epithelium.
Highlights
The main olfactory epithelium (OE), the primary sensory tissue responsible for olfaction, contains two or more stem and progenitor cell populations that establish, maintain, and reconstitute this tissue throughout the lifetime of an animal [1,2,3,4,5,6,7,8,9,10]
The results presented here provide novel insights into the regulation of olfactory epithelial assembly during embryonic development by analyzing the development and differentiation of the other, non-neuronal cell types of the Ascl1 knockout olfactory epithelium
The production of horizontal basal cells (HBCs) is aberrant but not aborted in the olfactory epithelium of Ascl1 knockout mice; as the population is still incomplete in agematched littermates when the mutant pups die or are killed perinatally, we cannot know whether or not HBC number might eventually catch-up in the knockout mice
Summary
The main olfactory epithelium (OE), the primary sensory tissue responsible for olfaction, contains two or more stem and progenitor cell populations that establish, maintain, and reconstitute this tissue throughout the lifetime of an animal [1,2,3,4,5,6,7,8,9,10]. The cascade of neurogenic basic-helix-loop-helix transcription factors triggered by ASCL1 expression ( known as MASH1) and the canonical Notch signaling pathway that directly or indirectly regulates that cascade play a key role in the development and regeneration of the OE [11,12,13,14,15]. Overexpression studies, and the changes in expression of multiple components of the pathway downstream of NOTCH following injury emphasize its importance in regulating olfactory epithelial cell fate – for example, the choice between generation of OSNs vs other cell types [11,12,13,14]. The previous work puts ASCL1 at a crucial choice point in olfactory neurogenesis, setting in motion a cascade of transcription factors that culminates in the production of OSNs. For example, NEUROG1 and NEUROD1 are downstream of ASCL1 on the basis of timing of expression and genetic epistasis
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