Expression patterns of basic helix-loop-helix transcription factors define subsets of olfactory progenitor cells.

Direct damage to the olfactory epithelium by inhalation of the olfactotoxin methyl bromide activates a population of multipotent globose basal cells, which reconstitute all depleted cell populations. Because members of the basic helix-loop-helix family of transcription factors are known to regulate neurogenesis and cell production, we performed in situ hybridization to examine the expression of several members of that family during the recovery of the rat olfactory epithelium after methyl bromide lesion. The numbers of basal cells expressing the proneural transcriptional activators Mash1, Neurogenin1, and NeuroD all fall precipitously 1 day after lesion. Mash1 levels begin to recover by 2 days, Neurogenin1 and NeuroD by 3 days, and substantial numbers of neurons reappear by 4 days. The antineurogenic factor Hes1 is limited to the sustentacular cells of the unlesioned olfactory epithelium and to the adjoining respiratory epithelium. Immediately after methyl bromide lesion, but not at any time after bulbectomy, a large fraction of residual, marker-confirmed globose basal cells initiate expression of Hes1. Subsequently, the Hes1-positive cells lose their association with the basal lamina, shift apically, and differentiate into sustentacular cells. In contrast, Hes5 is expressed by a small subset of globose basal cells and by olfactory ensheathing glia in the normal mucosa; Hes5 label disappears from both transiently after lesion. In sum, the recovery of the neuronal population after peripheral lesion recapitulates the sequence of transcription factor expression observed during embryonic development of the epithelium. Moreover, expression of Hes1 marks that population of globose basal cells committed to making sustentacular cells after methyl bromide lesion.