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

Coffin-Siris 综合征小鼠模型的发育生物学和行为改变

• 批准号: 451025214
• 负责人: Professorin Dr. Ulrike Nuber
• 金额: --
• 依托单位: Arbeitsgruppe Stem Cell and Developmental Biology
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/451025214?language=en
• 关键词: Developmental; biology; behavioral; alterations; mouse

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.

SMARCB1(SWI/SNF相关的基质相关肌动蛋白依赖的染色质亚家族B成员1)蛋白是染色质重构复合体的核心成分。这些复合体在发育过程中基因活动的建立和维持中起着至关重要的作用。SMARCB1基因杂合胚系突变可导致神经发育障碍、Coffin-Siris综合征(CSS)和SMARCB1相关智能障碍(ID)伴脉络丛增生(CPH)。我们已经培育出第一个SMARCB1突变小鼠模型，其脑部表型为SMARCB1相关的CSS和ID-CPH，尤其是影响前后轴不同大脑区域的中线缺陷(Filatova等人，《自然通讯》2019)。基于对SMARCB1突变动物的详细组织学分析，我们发现在患有CS和ID-CPH的儿童中存在迄今未被认识到的广泛的中线缺陷。这一新知识有助于改进临床诊断和分类。SMARCB1突变是如何导致CS和SMARCB1相关ID-CPH的各种中线缺陷的完全未知的。在这个项目中，我们将a)使用SMARCB1突变小鼠模型来阐明当SMARCB1在大脑中失去功能时发生的分子和细胞后果以及与脑中线缺陷相关的分子和细胞后果。此外，我们将b)定量描述SMARCB1突变小鼠的行为特征。