奥地利科学院分子生物技术研究所Jürgen A. Knoblich和Nina S. Corsini课题组报道，在人类胼胝体类器官模型中，ARID1B控制轴突投射的转录程序。这一研究成果于2024年5月7日发表在国际顶尖学术期刊《细胞—干细胞》上。

该团队发现表达SATB2的神经元在ARID1B^+/-神经类器官成熟受损，SATB2是胼胝体投射神经元(CPN)身份的决定因素。从分子上讲，TCF样、NFI样和ARID样转录因子靶向的基因组区域染色质可及性的降低，驱动了胼胝体(CC)发育所需基因的差异表达。

通过胼胝体束的体外模型，研究人员证明了这种转录失调损害了远程轴突投射的形成，导致结构连接不足。他们的研究揭示了mSWI/SNF在人类皮质发生中的新功能，确定了SATB2+神经元的细胞自主轴突发生缺陷是ARID1B患者胼胝体发育不全的一个原因。

据了解，作为mSWI/SNF复合体的一员，ARID1B的突变在人类中引发了严重的神经发育表型，但是机制并不清楚。ARID1B患者大脑中最常见的结构异常是胼胝体发育不全(ACC)，其特征是缺少连接远端皮层区域的半球间白质束。

附：英文原文

Title: ARID1B controls transcriptional programs of axon projection in an organoid model of the human corpus callosum

Author: Catarina Martins-Costa, Andrea Wiegers, Vincent A. Pham, Jaydeep Sidhaye, Balint Doleschall, Maria Novatchkova, Thomas Lendl, Marielle Piber, Angela Peer, Paul Mseneder, Marlene Stuempflen, Siu Yu A. Chow, Rainer Seidl, Daniela Prayer, Romana Hftberger, Gregor Kasprian, Yoshiho Ikeuchi, Nina S. Corsini, Jürgen A. Knoblich

Issue&Volume: 2024-05-07

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.

DOI: 10.1016/j.stem.2024.04.014

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(24)00141-3