Neurog1 and Neurog2 coordinately regulate development of the olfactory system.

BACKGROUND:Proneural genes encode basic helix-loop-helix transcription factors that specify distinct neuronal identities in different regions of the nervous system. In the embryonic telencephalon, the proneural genes Neurog1 and Neurog2 specify a dorsal regional identity and glutamatergic projection neuron phenotype in the presumptive neocortex, but their roles in cell fate specification in the olfactory bulb, which is also partly derived from dorsal telencephalic progenitors, have yet to be assessed. Given that olfactory bulb development is guided by interactions with the olfactory epithelium in the periphery, where proneural genes are also expressed, we investigated the roles of Neurog1 and Neurog2 in the coordinated development of these two olfactory structures. RESULTS:Neurog1/2 are co-expressed in olfactory bulb progenitors, while only Neurog1 is widely expressed in progenitors for olfactory sensory neurons in the olfactory epithelium. Strikingly, only a remnant of an olfactory bulb forms in Neurog1-/-;Neurog2-/- double mutants, while this structure is smaller but distinguishable in Neurog1-/- single mutants and morphologically normal in Neurog2-/- single mutants. At the cellular level, fewer glutamatergic mitral and juxtaglomerular cells differentiate in Neurog1-/-;Neurog2-/- double-mutant olfactory bulbs. Instead, ectopic olfactory bulb interneurons are derived from dorsal telencephalic lineages in Neurog1-/-;Neurog2-/- double mutants and to a lesser extent in Neurog2-/- single mutants. Conversely, cell fate specification is normal in Neurog1-/- olfactory bulbs, but aberrant patterns of cell proliferation and neuronal migration are observed in Neurog1-/- single and Neurog1-/-;Neurog2-/- double mutants, probably contributing to their altered morphologies. Finally, in Neurog1-/- and Neurog1-/-;Neurog2-/- embryos, olfactory sensory neurons in the epithelium, which normally project to the olfactory bulb to guide its morphogenesis, fail to innervate the olfactory bulb. CONCLUSIONS:We have identified a cell autonomous role for Neurog1/2 in specifying the glutamatergic identity of olfactory bulb neurons. Furthermore, Neurog1 (and not Neurog2) is required to guide olfactory sensory neuron innervation of the olfactory bulb, the loss of which results in defects in olfactory bulb proliferation and tissue morphogenesis. We thus conclude that Neurog1/2 together coordinate development of the olfactory system, which depends on tissue interactions between the olfactory bulb and epithelium.

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