染色质重塑基因ARID1A的功能缺失突变是Coffin-Siris综合征的一个原因,以call体发育不全为特征的发育障碍。这里,我们描述了Arid1a在皮质发育过程中的功能,并意外地发现Arid1a在亚板神经元(SPN)中的选择性作用。SPNs,策略性地定位在皮质灰质和白质的界面,协调神经电路布线不可或缺的多个发展过程。我们发现Arid1a的全皮质缺失会导致皮质内轴突的广泛定位错误和call体的发育不全。稀疏Arid1a删除,然而,不会自主地误行call骨轴突,在轴突导向中涉及非细胞自主Arid1a功能。支持这种可能性,丘脑皮质神经元的上升轴突,不受皮质Arid1a缺失的自主影响,在它们进入皮层和胡须桶的神经支配方面也受到了干扰。与这些错误的表型相吻合,让人想起底板消融,我们发现Arid1a缺失后SPN基因表达的选择性丧失。此外,SPN的多个特性对其布线功能至关重要,包括子板组织,亚板轴突-丘脑皮质轴突共索(“握手”),和细胞外基质,受到严重干扰。为了实证检验子板块中的Arid1a充分性,我们产生了一个皮质板缺失的Arid1a,它没有SPN。在这个模型中,亚板Arid1a表达对于亚板组织是足够的,亚板轴突-丘脑皮质轴突共束结扎,和亚板细胞外基质。与这些接线功能一致,子板Arid1a足以形成正常的call骨,丘脑皮质轴突靶向,和晶须桶的发展。因此,Arid1a是皮质电路布线必不可少的子板相关引导机制的多功能调节器。
Loss-of-function mutations in chromatin remodeler gene ARID1A are a cause of Coffin-Siris syndrome, a developmental disorder characterized by dysgenesis of corpus callosum. Here, we characterize Arid1a function during cortical development and find unexpectedly selective roles for Arid1a 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 Arid1a leads to extensive mistargeting of intracortical axons and agenesis of corpus callosum. Sparse Arid1a deletion, however, does not autonomously misroute callosal axons, implicating noncell-autonomous Arid1a functions in axon guidance. Supporting this possibility, the ascending axons of thalamocortical neurons, which are not autonomously affected by cortical Arid1a 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 Arid1a 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 Arid1a sufficiency in subplate, we generate a cortical plate deletion of Arid1a that spares SPNs. In this model, subplate Arid1a expression is sufficient for subplate organization, subplate axon-thalamocortical axon cofasciculation, and subplate extracellular matrix. Consistent with these wiring functions, subplate Arid1a sufficiently enables normal callosum formation, thalamocortical axon targeting, and whisker barrel development. Thus, Arid1a is a multifunctional regulator of subplate-dependent guidance mechanisms essential to cortical circuit wiring.