Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109.
Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109.
Proc Natl Acad Sci U S A. 2021 May 25;118(21). doi: 10.1073/pnas.2100686118.
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.
染色质重塑基因 功能丧失突变是 Coffin-Siris 综合征的一个病因，这是一种以胼胝体发育不良为特征的发育障碍。在这里，我们描述了 在皮质发育过程中的功能，并出人意料地发现 在基板神经元 (SPN) 中有选择性作用。SPN 位于皮质灰白质交界处，策略性地定位，协调多个对神经回路布线不可或缺的发育过程。我们发现皮质全缺失 会导致皮质内轴突广泛靶向错误和胼胝体缺失。然而，稀疏的 缺失不会自主地使胼胝体轴突迷路，暗示在轴突导向中有非细胞自主的 功能。支持这种可能性，丘脑皮质神经元的上升轴突，它们不受皮质 缺失的自主影响，在它们进入皮质和支配胡须桶的神经支配的路径中也被中断。与这些布线表型一致，这些表型类似于基板消融，我们在非偏倚的情况下发现 缺失后 SPN 基因表达的选择性丢失。此外，对 SPN 布线功能至关重要的多个 SPN 特征，包括基板组织、基板轴突-丘脑皮质轴突共融合 ("握手") 和细胞外基质，都受到严重破坏。为了在基板中进行经验性测试 ，我们生成了一个皮质板缺失的 ，保留了 SPN。在这个模型中，基板 表达足以维持基板组织、基板轴突-丘脑皮质轴突共融合和基板细胞外基质。与这些布线功能一致，基板 足以使正常的胼胝体形成、丘脑皮质轴突靶向和胡须桶发育。因此， 是基板依赖性导向机制的多功能调节剂，对皮质回路布线至关重要。
