<i>Ascl1</i>is required to specify a subset of ventromedial hypothalamic neurons

Abstract

Despite clear physiological roles, the ventromedial hypothalamus (VMH) developmental programs are poorly understood. Here, we asked whether the proneural gene achaete-scute homolog 1 (<i>Ascl1</i>) contributes to VMH development. <i>Ascl1</i> transcripts were detected in embryonic day (E) 10.5 to postnatal day 0 VMH neural progenitors. The elimination of <i>Ascl1</i> reduced the number of VMH neurons at E12.5 and E15.5, particularly within the VMH-central (VMH_C) and -dorsomedial (VMH_DM) subdomains, and resulted in a VMH cell fate change from glutamatergic to GABAergic. We observed a loss of <i>Neurog3</i> expression in <i>Ascl1^-/-</i> hypothalamic progenitors and an upregulation of <i>Neurog3</i> when <i>Ascl1</i> was overexpressed. We also demonstrated a glutamatergic to GABAergic fate switch in <i>Neurog3</i>-null mutant mice, suggesting that <i>Ascl1</i> might act via <i>Neurog3</i> to drive VMH cell fate decisions. We also showed a concomitant increase in expression of the central GABAergic fate determinant <i>Dlx1/2</i> in the <i>Ascl1-</i>null hypothalamus. However, <i>Ascl1</i> was not sufficient to induce an ectopic VMH fate when overexpressed outside the normal window of competency. Combined, <i>Ascl1</i> is required but not sufficient to specify the neurotransmitter identity of VMH neurons, acting in a transcriptional cascade with <i>Neurog3</i>.