Abstract
Accurate and precise regulation of gene expression is necessary to ensure proper brain development and plasticity across the lifespan. As an ATP-dependent chromatin-remodeling complex, the BAF (Brg1 Associated Factor) complex can alter histone-DNA interactions, facilitating dynamic changes in gene expression by controlling DNA accessibility to the transcriptional machinery. Mutations in 12 of the potential 29 subunit genes that compose the BAF nucleosome remodeling complex have been identified in several developmental disorders including Autism spectrum disorders (ASD) and intellectual disability. A novel, neuronal version of BAF (nBAF) has emerged as promising candidate in the development of ASD as its expression is tied to neuron differentiation and it’s hypothesized to coordinate expression of synaptic genes across brain development. Recently, mutations in BAF53B, one of the neuron specific subunits of the nBAF complex, have been identified in patients with ASD and Developmental and epileptic encephalopathy-76 (DEE76), indicating BAF53B is essential for proper brain development. Recent work in cultured neurons derived from patients with BAF53B mutations suggests links between loss of nBAF function and neuronal dendritic spine formation. Deletion of one or both copies of mouse Baf53b disrupts dendritic spine development, alters actin dynamics and results in fewer synapses in vitro. In the mouse, heterozygous loss of Baf53b severely impacts synaptic plasticity and long-term memory that is reversible with reintroduction of Baf53b or manipulations of the synaptic plasticity machinery. Furthermore, surviving Baf53b-null mice display ASD-related behaviors, including social impairments and repetitive behaviors. This review summarizes the emerging evidence linking deleterious variants of BAF53B identified in human neurodevelopmental disorders to abnormal transcriptional regulation that produces aberrant synapse development and behavior.
Highlights
Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder characterized by deficits in communication and social interactions, as well as by repetitive or restricted behaviors and intellectual disability (ID) (Sharma et al, 2018; Lord et al, 2020)
Baf53b in Autism Spectrum Disorder any single gene mutation accounting for only 0.5–2% of ASD cases (Devlin and Scherer, 2012)
Chromatin remodeling complexes use the energy of ATP to slide, evict, or restructure nucleosomes in concert with other regulatory factors to control access to the DNA and gene expression (Clapier and Cairns, 2009)
Summary
Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder characterized by deficits in communication and social interactions, as well as by repetitive or restricted behaviors and intellectual disability (ID) (Sharma et al, 2018; Lord et al, 2020). Induced pluripotent stem cell (iPSC) derived neurons from patients with the c.1279del (p.∗427Aspext∗33) recessive BAF53B mutation had almost a complete loss of MAP2 (a marker of neuronal branching) and increased nuclei size at 15DIV (days in vitro), similar to that of BAF53B KO neurons (Wenderski et al, 2020) This mutation occurs in the final exon of BAF53B and protein expression is retained in these cells (Bell et al, 2019). The mutant protein failed to incorporate into the BAF complex and resulting in defective nBAF complexes lacking BAF53B (Wenderski et al, 2020) This data further supports the idea that recessive mutations that occur before the final exon of the BAF53B coding region result in mRNA destabilization and non-sense mediated decay. RNAi knockdown of Brg, Baf, and Baf45b in Baf53b−/− neurons did not Frontiers in Molecular Neuroscience | www.frontiersin.org
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