The remodeling of chromatin is essential to orchestrate gene expression programs during development, especially in the nervous system. The BAF (BRG1/BRM-associated factor) complex, an ATP-dependent chromatin remodeling complex, is crucial for neuronal differentiation and brain development. Among its different subunits, the SMARCD family (SMARCD1, SMARCD2, SMARCD3) plays a role in neurodevelopment, a role that remains poorly understood. In this thesis, I investigated the functions and compensatory dynamics of the SMARCD paralogs using mouse embryonic stem cells (mESCs), induced neuron models (iNeurons), and in vivo knockout (KO) embryos.

Through CRISPR-Cas9-mediated knockouts, I showed that SMARCD1 and SMARCD2 cooperatively maintain pluripotency and repress premature differentiation. Their double KO led to growth defects and a shift toward meso/endodermal lineages. In contrast, most single and double KO in mESCs and iNeurons showed minimal phenotypes and transcriptional changes, indicating a strong compensation among the paralogs at the protein level. SMARCD2 displayed a dynamic regulation in response to the loss of other subunits.

In vivo analysis of SMARCD1/3 double KO embryos revealed an overall preserved cortical architecture but some alterations in neuronal maturation, suggesting a cooperative role during the development of the brain. These findings support the existence of a robust but imperfect compensatory mechanism among the SMARCD paralogs, which may be insufficient in humans as pathogenic mutations in individual subunits are associated with neurodevelopmental disorders. This master thesis provides new insights into the context dependent roles and redundancy of chromatin remodelers in development and disease.