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

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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.