A non-canonical role for the proneural gene<i>Neurog1</i>as a negative regulator of neocortical neurogenesis

Abstract

Neural progenitors undergo temporal identity transitions to sequentially generate the neuronal and glial cells that make up the mature brain. Proneural genes have well characterized roles in promoting neural cell differentiation and subtype specification, but they also regulate the timing of identity transitions through poorly understood mechanisms. Here we investigated how the highly-related proneural genes Neurog1 and Neurog2 interact to control the timing of neocortical neurogenesis. We found that Neurog1 acts in an atypical fashion as it is required to suppress rather than promote neuronal differentiation in early corticogenesis. In Neurog1−/− neocortices, early-born neurons differentiate in excess, while in vitro, Neurog1−/− progenitors have a decreased propensity to proliferate and form neurospheres. Instead, Neurog1−/− progenitors preferentially generate neurons, a phenotype restricted to the Neurog2+ progenitor pool. Mechanistically, Neurog1 and Neurog2 heterodimerize, and while Neurog1 and Neurog2 individually promote neurogenesis, misexpression together blocks this effect. Finally, Neurog1 is also required to induce the expression of neurogenic factors (Dll1, Hes5) and repress the expression of neuronal differentiation genes (Fezf2, Neurod6). Neurog1 thus employs different mechanisms to temper the pace of early neocortical neurogenesis.