Chromatin remodeler regulates subplate neuron identity and wiring of cortical connectivity.

Loss-of-function mutations in chromatin remodeler gene are a cause of Coffin-Siris syndrome, a developmental disorder characterized by dysgenesis of corpus callosum. Here, we characterize function during cortical development and find unexpectedly selective roles for in subplate neurons (SPNs). SPNs, strategically positioned at the interface of cortical gray and white matter, orchestrate multiple developmental processes indispensable for neural circuit wiring. We find that pancortical deletion of leads to extensive mistargeting of intracortical axons and agenesis of corpus callosum. Sparse deletion, however, does not autonomously misroute callosal axons, implicating noncell-autonomous functions in axon guidance. Supporting this possibility, the ascending axons of thalamocortical neurons, which are not autonomously affected by cortical deletion, are also disrupted in their pathfinding into cortex and innervation of whisker barrels. Coincident with these miswiring phenotypes, which are reminiscent of subplate ablation, we unbiasedly find a selective loss of SPN gene expression following deletion. In addition, multiple characteristics of SPNs crucial to their wiring functions, including subplate organization, subplate axon-thalamocortical axon cofasciculation ("handshake"), and extracellular matrix, are severely disrupted. To empirically test sufficiency in subplate, we generate a cortical plate deletion of that spares SPNs. In this model, subplate expression is sufficient for subplate organization, subplate axon-thalamocortical axon cofasciculation, and subplate extracellular matrix. Consistent with these wiring functions, subplate sufficiently enables normal callosum formation, thalamocortical axon targeting, and whisker barrel development. Thus, is a multifunctional regulator of subplate-dependent guidance mechanisms essential to cortical circuit wiring.