Chromatin remodeler <i>Arid1a</i> regulates subplate neuron identity and wiring of cortical connectivity.

Abstract

Loss-of-function mutations in chromatin remodeler gene <i>ARID1A</i> are a cause of Coffin-Siris syndrome, a developmental disorder characterized by dysgenesis of corpus callosum. Here, we characterize <i>Arid1a</i> function during cortical development and find unexpectedly selective roles for <i>Arid1a</i> 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 <i>Arid1a</i> leads to extensive mistargeting of intracortical axons and agenesis of corpus callosum. Sparse <i>Arid1a</i> deletion, however, does not autonomously misroute callosal axons, implicating noncell-autonomous <i>Arid1a</i> functions in axon guidance. Supporting this possibility, the ascending axons of thalamocortical neurons, which are not autonomously affected by cortical <i>Arid1a</i> 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 <i>Arid1a</i> 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 <i>Arid1a</i> sufficiency in subplate, we generate a cortical plate deletion of <i>Arid1a</i> that spares SPNs. In this model, subplate <i>Arid1a</i> expression is sufficient for subplate organization, subplate axon-thalamocortical axon cofasciculation, and subplate extracellular matrix. Consistent with these wiring functions, subplate <i>Arid1a</i> sufficiently enables normal callosum formation, thalamocortical axon targeting, and whisker barrel development. Thus, <i>Arid1a</i> is a multifunctional regulator of subplate-dependent guidance mechanisms essential to cortical circuit wiring.