The role of BAF (mSWI/SNF) complexes in mammalian neural development

Abstract

The BAF (mammalian SWI/SNF) complexes are a family of multi-subunit ATP-dependent chromatin remodelers that use ATP hydrolysis to alter chromatin structure. Distinct BAF complex compositions are possible through combinatorial assembly of homologous subunit families and can serve non-redundant functions. In mammalian neural development, developmental stage-specific BAF assemblies are found in embryonic stem cells, neural progenitors and postmitotic neurons. In particular, the neural progenitor-specific BAF complexes are essential for controlling the kinetics and mode of neural progenitor cell division, while neuronal BAF function is necessary for the maturation of postmitotic neuronal phenotypes as well as long-term memory formation. The microRNA-mediated mechanism for transitioning from npBAF to nBAF complexes is instructive for the neuronal fate and can even convert fibroblasts into neurons. The high frequency of BAF subunit mutations in neurological disorders underscores the rate-determining role of BAF complexes in neural development, homeostasis, and plasticity.

Keywords: BAF; Coffin-Siris syndrome; Nicolaides-Baraitser syndrome; autism; chromatin remodeling; intellectual disability; mammalian SWI/SNF; microRNA; neural development; schizophrenia.

Figure 1. BAF complex assemblies in neural development

Distinct BAF compositions exist in ES cells (esBAF), neural progenitors (npBAF) and postmitotic neurons (nBAF). Each complex serves critical context-dependent functions by interacting with a unique set of cellular factors. During mitotic exit, miR-9* and miR-124 mediate switching at three subunit positions (highlighted in red and orange in esBAF/npBAF and nBAF, respectively).

Figure 2. Most commonly mutated BAF subunits in human cognitive disorders

Dominant de novo BAF subunit mutations have been found in Coffin-Siris syndrome (CSS), Nicolaides-Baraitser syndrome (NCBRS), sporadic intellectual disability (ID), autism spectrum disorder (ASD), schizophrenia (SZ) and Kleefstra syndrome. Mutations in BAF250A and BAF250B lead to truncated proteins, indicating that haploinsufficiency of these subunits causes disease. Mutations in the BRG1 and BRM ATPases as well as BAF57 and BAF47 are missense mutations or in-frame deletions, suggesting gain-of-function or dominant negative mechanisms. Microdeletions or translocations are not included. Data taken from the following studies: Hoyer et al. (2012); Kleefstra T. Am J Hum Genet (2012); Koga et al. (2009); Nord et al. (2011); Santen et al. (2012, ; Tsurusaki et al. (2012, ; Van Houdt et al. (2012); Wieczorek et al. (2013); Wolff et al. (2011).