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

Acta Neuropathologica Communications, vol. 14

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.

Authors 9

1. Alina Filatova

   Technische Universität Darmstadt

   Affiliation as printed

   Stem Cell and Development Biology, Technical University of Darmstadt;

2. Joanna Chiang

   Technische Universität Darmstadt

   Affiliation as printed

   Stem Cell and Development Biology, Technical University of Darmstadt;

3. Hannah North

   Technische Universität Darmstadt

   Affiliation as printed

   Stem Cell and Development Biology, Technical University of Darmstadt;

4. Myrthe R. M. Kamphof Aachen Clinical Neurodevelopmental Sciences

   Leiden University

   Affiliation as printed

   Clinical Neurodevelopmental Sciences, Leiden University;

5. Michaela Becker-Röck

   Technische Universität Darmstadt

   Affiliation as printed

   Stem Cell and Development Biology , Technical University of Darmstadt , 64287 Darmstadt , Germany

6. Bodo Laube

   Technische Universität Darmstadt

   Affiliation as printed

   Neurophysiology and Neurosensory Systems, Technical University of Darmstadt;

7. Gijs W.E. Santen Aachen Department of Clinical Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Clinical Genetics, Leiden University Medical Center

8. Swaab Hanna Aachen Clinical Neurodevelopmental Sciences

   Leiden University

   Affiliation as printed

   Clinical Neurodevelopmental Sciences, Leiden University;

9. Ulrike A. Nuber corresponding

   Technische Universität Darmstadt

   Affiliation as printed

   Stem Cell and Development Biology, Technical University of Darmstadt;