Dosage-dependent requirements of Magoh for cortical interneuron generation and survival

Embryonic interneuron development underlies cortical function and its disruption contributes to neurological disease. Yet, the mechanisms by which viable interneurons are produced from progenitors remain poorly understood. Here we demonstrate dosage dependent requirements of the exon junction complex component Magoh for interneuron genesis. Conditional Magoh ablation from interneuron progenitors, but not post-mitotic neurons, depletes cortical interneuron number through adulthood, with increased severity in homozygotes. Using live imaging we discover that Magoh deficiency delays progenitor mitotic progression in a dosage sensitive fashion, with 40% of homozygous progenitors failing to divide. This shows Magoh is required in progenitors for both generation and survival of newborn progeny. Transcriptome analysis implicates p53 signaling; Moreover, p53 ablation in Magoh haploinsufficient progenitors rescues apoptosis, completely recovering interneuron number. In striking contrast, in Magoh homozygotes, p53 loss fails to rescue interneuron number and mitotic delay, further implicating mitotic defects in interneuron loss. Our results demonstrate interneuron development is intimately dependent upon progenitor mitosis duration and uncover a critical post-transcriptional regulator of interneuron fate relevant for neurodevelopmental pathologies.