A subpopulation of cortical neurons altered by mutations in the autism risk gene DDX3X

Cell fate decisions during cortical development sculpt the identity of long-range connections that subserve complex behaviors. These decisions are largely dictated by mutually exclusive transcription factors, including CTIP2/Bcl11b for subcerebral projection neurons and BRN1/Pou3f3 for intra-telencephalic projection neurons. We have recently reported that the balance of cortical CTIP2-expressing neurons is altered in a mouse model of DDX3X syndrome, a female-biased neurodevelopmental disorder associated with intellectual disability, autism spectrum disorder, and significant motor challenges. Here, we studied the developmental dynamics of a subpopulation of cortical neurons co-expressing CTIP2 and BRN1. We found that CTIP2+BRN1+ neurons are born during early phases of neurogenesis like other CTIP2+ neurons, peak in expression during perinatal life, and persist in adult brains. We also found that CTIP2+BRN1+ neurons are excessive in number in prenatal and mature cortical motor areas of Ddx3x mutant mice, translating into altered laminar distribution of subcerebral projection neurons extending axons to the brainstem. These findings underscore the critical role of molecular specification during cortical development in health and disease.