Lineage, Identity, and Fate of Distinct Progenitor Populations in the Embryonic Olfactory Epithelium

We defined a temporal dimension of precursor diversity and lineage in the developing mouse olfactory epithelium (OE) at mid-gestation that results in genesis of distinct cell classes. Slow, symmetrically dividing Meis1+/ Pax7+ progenitors in the early differentiating lateral OE give rise to small numbers of Ascl1+ precursors in the dorsolateral and ventromedial OE. Few of the initial progeny of the Ascl1+ precursors immediately generate olfactory receptor neurons (ORNs). Instead, most early progeny of this temporally defined precursor cohort, labeled via temporally discreet tamoxifen-dependent Ascl1Cre-driven recombination, populate a dorsomedial OE domain comprised of proliferative Ascl1+ as well as Ascl1-cells from which newly generated ORNs are mostly excluded. The most prominent early progeny of these Ascl1+ OE precursors are migratory mass cells associated with the nascent olfactory nerve (ON) in the frontonasal mesenchyme. These temporal, regional and lineage distinctions are matched by differences in proliferative capacity and modes of division in isolated, molecularly distinct lateral versus medial OE precursors. By late gestation, the progeny of the temporally and spatially defined Ascl1+ precursor cohort include few proliferating precursors. Instead, these cells generate a substantial subset of OE sustentacular cells, spatially restricted ORNs, and ensheathing cells associated with actively growing as well as mature ON axons. Accordingly, from the earliest stages of OE differentiation, distinct temporal and spatial precursor identities provide a template for acquisition of subsequent OE and ON cellular diversity.