title: Ascl1 (Mash1) knockout perturbs differentiation of nonneuronal cells in olfactory epithelium.
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.
authors.affiliation: Department of Anatomy and Cellular Biology, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Krolewski
authors.forename: Adam
authors.initials: A
authors.lastname: Packard
authors.forename: Woochan
authors.initials: W
authors.lastname: Jang
authors.forename: Hendrik
authors.initials: H
authors.lastname: Wildner
authors.forename: James E
authors.initials: JE
authors.lastname: Schwob
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000378:metabolism; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis; D009831:Olfactory Mucosa / Q000166:cytology* / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D019009:Proto-Oncogene Proteins c-kit; D051881:Receptor, Notch1; D055748:SOXB1 Transcription Factors; D000072056:Transcription Factor HES-1; C499317:Ascl1 protein, mouse; C489734:Hes1 protein, mouse; C497762:Notch1 protein, mouse; C527783:Sox2 protein, mouse