Ctip1 Regulates the Balance between Specification of Distinct Projection Neuron Subtypes in Deep Cortical Layers

The molecular linkage between neocortical projection neuron subtype and area development, which enables the establishment of functional areas by projection neuron populations appropriate for specific sensory and motor functions, is poorly understood. Here, we report that Ctip1 controls precision of neocortical development by regulating subtype identity in deep-layer projection neurons. Ctip1 is expressed by postmitotic callosal and corticothalamic projection neurons but is excluded over embryonic development from corticospinal motor neurons, which instead express its close relative, Ctip2. Loss of Ctip1 function results in a striking bias in favor of subcerebral projection neuron development in sensory cortex at the expense of corticothalamic and deep-layer callosal development, while misexpression of Ctip1 in vivo represses subcerebral gene expression and projections. As we report in a paired paper, Ctip1 also controls acquisition of sensory area identity. Therefore, Ctip1 couples subtype and area specification, enabling specific functional areas to organize precise ratios of appropriate output projections. Woodworth et al. demonstrate that the transcription factor Ctip1 is necessary for the postmitotic development of corticothalamic, callosal, and subcerebral projection neurons. These important subtypes connect the deep layers of the neocortex with other brain regions, and Ctip1 function ensures that they are produced in appropriate locations and proportions.