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

IF 19.8 1区 医学 Q1 CELL & TISSUE ENGINEERING
Catarina Martins-Costa, Andrea Wiegers, Vincent A. Pham, Jaydeep Sidhaye, Balint Doleschall, Maria Novatchkova, Thomas Lendl, Marielle Piber, Angela Peer, Paul Möseneder, Marlene Stuempflen, Siu Yu A. Chow, Rainer Seidl, Daniela Prayer, Romana Höftberger, Gregor Kasprian, Yoshiho Ikeuchi, Nina S. Corsini, Jürgen A. Knoblich
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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.

Abstract Image

ARID1B控制人类胼胝体器官模型中轴突投射的转录程序
ARID1B是mSWI/SNF复合体的一个成员,它的突变会导致人类严重的神经发育表型,其机制难以捉摸。ARID1B 患者大脑中最常见的结构异常是胼胝体(ACC)缺失,其特征是大脑半球间没有连接远处皮质区域的白质束。在这里,我们发现表达 SATB2(胼胝体投射神经元(CPN)特性的决定因素)的神经元在 ARID1B+/- 神经器官组织中的成熟度受损。从分子角度看,TCF 样、NFI 样和 ARID 样转录因子靶标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。通过一个体外的 CC 道模型,我们证明了这种转录失调会损害长距离轴突投射的形成,从而导致结构上的连接不足。我们的研究揭示了 mSWI/SNF 在人类皮质发育过程中的新功能,确定了 SATB2+ 神经元的细胞自主轴突生长缺陷是 ARID1B 患者 ACC 的病因之一。
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来源期刊
Cell stem cell
Cell stem cell 生物-细胞生物学
CiteScore
37.10
自引率
2.50%
发文量
151
审稿时长
42 days
期刊介绍: Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.
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