# Chromatin remodelling subunit SMARCB1 is implicated in dendrite development and complex brain functions

## TL;DR

This study shows how a chromatin remodeling protein, SMARCB1, is important for brain development and function, and its dysfunction may lead to neurodevelopmental disorders like Coffin-Siris syndrome.

## Contribution

The study links SMARCB1 to dendrite development and brain function using a mouse model and human data, revealing potential mechanisms for associated cognitive and behavioral impairments.

## Key findings

- Smarcb1 mutant mice showed impaired motor coordination, spatial memory, and anxiety-like behaviors.
- Human individuals with SMARCB1 mutations exhibited similar cognitive and behavioral deviations.
- Reduced dendritic complexity and altered Wasl transcripts suggest disrupted actin polymerization in brain dysfunction.

## Abstract

SMARCB1 encodes a core component of the BAF chromatin remodelling complex and pathogenic variants in this gene are associated with neurodevelopmental disorders such as Coffin-Siris syndrome and intellectual disability with choroid plexus hyperplasia. The relationship between reduced or dysfunctional SMARCB1 protein products and severe functional brain changes associated with Coffin-Siris syndrome, including intellectual disability and severely delayed language and motor development, remains largely unknown. We performed cellular, molecular, and behavioural analyses of a Coffin-Siris syndrome mouse model with a heterozygous nervous system-specific Smarcb1 mutation. In addition, we evaluated general cognitive abilities, as well as cognitive and behavioural functioning, in individuals with SMARCB1-related Coffin-Siris syndrome. Smarcb1 mutant mice exhibited deficits in fine motor coordination and balance, as well as impaired spatial learning and memory. Furthermore, these mice showed anxiety-like behaviours and agitation when exposed to novel environments. The detected behavioural abnormalities could indicate impaired decision-making, which results in impaired risk assessment. Comparable cognitive and behavioural deviations were identified in individuals with Coffin-Siris syndrome and SMARCB1 pathogenic variants. Histological analyses revealed structural alterations in the brain of the Smarcb1 mouse model, including decreased dendritic length and complexity of dendritic trees. These alterations may explain the observed functional impairments. Notably, our finding of reduced Wasl transcripts in mutant Purkinje cell nuclei suggests that dysregulation of actin polymerization may be involved in the discovered dendritic defects. Taken together, we demonstrate a link between the chromatin remodelling complex component SMARCB1, complex brain functions, neuronal structure, and a key regulator of actin branching.

The online version contains supplementary material available at 10.1186/s40478-026-02258-2.