Significance This study addresses how the cerebral cortex is partitioned into specialized areas during development. Although both early embryonic patterning and postnatal synaptic input from sensory thalamic nuclei are known to be critical, early roles of thalamic axons in area-specific regulation of cortical neurogenesis are poorly understood. We examined this by developing a genetic mouse model in which thalamocortical projections fail to properly form during embryogenesis, and found these axons are required not only for an enhanced production of superficial layer neurons but also for promoting the layer 4 cell fate, a hallmark of the primary sensory cortex. These findings provide a mechanism by which thalamocortical axons complement the intrinsic programs of neurogenesis and early fate specification.

Area-specific axonal projections from the mammalian thalamus shape unique cellular organization in target areas in the adult neocortex. How these axons control neurogenesis and early neuronal fate specification is poorly understood. By using mutant mice lacking the majority of thalamocortical axons, we show that these axons increase the number of layer 4 neurons in primary sensory areas by enhancing neurogenesis and shifting the fate of superficial layer neurons to that of layer 4 by the neonatal stage. Part of these area-specific roles are played by the thalamus-derived molecule, VGF. Our work reveals that extrinsic cues from sensory thalamic projections have an early role in the formation of cortical cytoarchitecture by enhancing the production and specification of layer 4 neurons.