Developmental biology and behavioral alterations in a mouse model of Coffin-Siris syndrome

SMARCB 1（SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1）蛋白是BAF（BRG 1/BRM-associated factor）染色质重塑复合物的核心组分。这些复合物在发育过程中基因活性的建立和维持中起着至关重要的作用。SMARCB 1基因中的杂合子种系突变可导致神经发育障碍、Coffin-Siris综合征（CSS）和SMARCB 1相关的智力障碍（ID）伴脉络丛增生（CPH）。我们已经产生了第一个具有SMARCB 1相关CSS和ID-CPH的脑表型的Smarcb 1突变小鼠模型，特别是影响沿着前后轴的各种脑区域的中线缺陷（Filatova等人，Nature Communications 2019）。基于对Smarcb 1突变动物的详细组织学分析，我们发现了CSS和ID-CPH儿童中迄今未被认识的广泛中线缺陷。这些新知识有助于改进临床诊断和分类。SMARCB 1突变如何导致CSS和SMARCB 1相关ID-CPH的各种中线缺陷是完全未知的。在这个项目中，我们将a）使用Smarcb 1突变小鼠模型来阐明Smarcb 1功能丧失后发生的分子和细胞后果，这些后果与脑中线缺陷有关。此外，我们将B）定量描述Smarcb 1突变小鼠的行为显著性。

The SMARCB1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1) protein is a core component of BAF (BRG1/BRM-associated factor) chromatin remodeling complexes. These complexes play an essential role in the establishment and maintenance of gene activities during development. Heterozygous germline mutations in the SMARCB1 gene can cause neurodevelopmental disorders, Coffin-Siris syndrome (CSS) and SMARCB1-related intellectual disorder (ID) with choroid plexus hyperplasia (CPH). We have generated the first Smarcb1 mutant mouse model with brain phenotypes of SMARCB1-related CSS and ID-CPH, in particular midline defects affecting various brain regions along the anterior-posterior axis (Filatova et al., Nature Communications 2019). Based on detailed histological analyses of Smarcb1 mutant animals, we discovered a hitherto unrecognized broad spectrum of midline defects in children with CSS and ID-CPH. This new knowledge contributes to improved clinical diagnostics and classification. How SMARCB1 mutations lead to the various midline defects in CSS and SMARCB1-related ID-CPH is entirely unknown.In this project, we will a) use the Smarcb1 mutant mouse model to elucidate molecular and cellular consequences that occur upon loss of Smarcb1 function in the brain and that are associated with brain midline defects. Moreover, we will b) quantitatively describe behavioral conspicuities of Smarcb1 mutant mice.