Neurog1 and Neurog2 coordinately regulate development of the olfactory system

Abstract

AbstractBackgroundProneural 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 genesNeurog1andNeurog2specify 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 ofNeurog1andNeurog2in the coordinated development of these two olfactory structures.ResultsNeurog1/2are co-expressed in olfactory bulb progenitors, while onlyNeurog1is widely expressed in progenitors for olfactory sensory neurons in the olfactory epithelium. Strikingly, only a remnant of an olfactory bulb forms inNeurog1−/−;Neurog2−/−double mutants, while this structure is smaller but distinguishable inNeurog1−/−single mutants and morphologically normal inNeurog2−/−single mutants. At the cellular level, fewer glutamatergic mitral and juxtaglomerular cells differentiate inNeurog1−/−;Neurog2−/−double-mutant olfactory bulbs. Instead, ectopic olfactory bulb interneurons are derived from dorsal telencephalic lineages inNeurog1−/−;Neurog2−/−double mutants and to a lesser extent inNeurog2−/−single mutants. Conversely, cell fate specification is normal inNeurog1−/−olfactory bulbs, but aberrant patterns of cell proliferation and neuronal migration are observed inNeurog1−/−single andNeurog1−/−;Neurog2−/−double mutants, probably contributing to their altered morphologies. Finally, inNeurog1−/−andNeurog1−/−;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.ConclusionsWe have identified a cell autonomous role forNeurog1/2 in specifying the glutamatergic identity of olfactory bulb neurons. Furthermore,Neurog1(and notNeurog2) 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 thatNeurog1/2together coordinate development of the olfactory system, which depends on tissue interactions between the olfactory bulb and epithelium.