Abstract：
Mutations in ARID1B, a member of the mSWI/SNF complex, cause severe neurodevelopmental phenotypes with elusive mechanisms in humans. The most common structural abnormality in the brain of ARID1B patients is agenesis of the corpus callosum (ACC), characterized by the absence of an interhemispheric white matter tract that connects distant cortical regions. Here, we find that neurons expressing SATB2, a determinant of callosal projection neuron (CPN) identity, show impaired maturation in ARID1B+/- neural organoids. Molecularly, a reduction in chromatin accessibility of genomic regions targeted by TCF-like, NFI-like, and ARID-like transcription factors drives the differential expression of genes required for corpus callosum (CC) development. Through an in vitro model of the CC tract, we demonstrate that this transcriptional dysregulation impairs the formation of long-range axonal projections, causing structural underconnectivity. Our study uncovers new functions of the mSWI/SNF during human corticogenesis, identifying cell-autonomous axonogenesis defects in SATB2+ neurons as a cause of ACC in ARID1B patients.
摘要：
ARID1B突变，mSWI/SNF复合体的成员，在人类中引起严重的神经发育表型，机制难以捉摸。ARID1B患者大脑中最常见的结构异常是call体（ACC）的发育不全，其特征是没有连接远处皮质区域的半球间白质束。这里,我们发现表达SATB2的神经元是call体投射神经元（CPN）身份的决定因素，显示ARID1B+/-神经类器官的成熟受损。分子上，TCF样靶向基因组区域的染色质可及性降低，NFI-like,和ARID样转录因子驱动call体（CC）发育所需基因的差异表达。通过CC道的体外模型，我们证明了这种转录失调会损害长程轴突投射的形成，导致结构不连通。我们的研究揭示了mSWI/SNF在人类皮质发生过程中的新功能，在ARID1B患者中，确定SATB2+神经元中的细胞自主轴突生成缺陷是ACC的原因。
