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-characterised 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 <i>Neurog1</i> and <i>Neurog2</i> interact to control the timing of neocortical neurogenesis. We found that <i>Neurog1</i> acts in an atypical fashion as it is required to suppress rather than promote neuronal differentiation in early corticogenesis. In <i>Neurog1^-/-</i> neocortices, early born neurons differentiate in excess, whereas, <i>in vitro</i>, <i>Neurog1^-/-</i> progenitors have a decreased propensity to proliferate and form neurospheres<i>.</i> Instead, <i>Neurog1^-/-</i> progenitors preferentially generate neurons, a phenotype restricted to the <i>Neurog2</i>⁺ progenitor pool. Mechanistically, Neurog1 and Neurog2 heterodimerise, and while <i>Neurog1</i> and <i>Neurog2</i> individually promote neurogenesis, misexpression together blocks this effect. Finally, <i>Neurog1</i> is also required to induce the expression of neurogenic factors (<i>Dll1</i> and <i>Hes5</i>) and to repress the expression of neuronal differentiation genes (<i>Fezf2</i> and <i>Neurod6</i>). <i>Neurog1</i> thus employs different mechanisms to temper the pace of early neocortical neurogenesis.