Kinetic Analysis of npBAF to nBAF Switching Reveals Exchange of SS18 with CREST and Integration with Neural Developmental Pathways

Departments of Developmental Biology and Pathology, and Department of Genetics, Stanford University Medical School, Stanford, California 94305, and Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri 63110.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 06/2013; 33(25):10348-61. DOI: 10.1523/JNEUROSCI.1258-13.2013
Source: PubMed


During the development of the vertebrate nervous system, neural progenitors divide, generate progeny that exit mitosis, and then migrate to sites where they elaborate specific morphologies and synaptic connections. Mitotic exit in neurons is accompanied by an essential switch in ATP-dependent chromatin regulatory complexes from the neural progenitor Brg/Brm-associated factor (npBAF) to neuron-specific nBAF complexes that is in part driven by miR-9/9* and miR-124. Recapitulating this microRNA/chromatin switch in fibroblasts leads to their direct conversion to neurons. We have defined the kinetics of neuron-specific BAF complex assembly in the formation of induced neurons from mouse embryonic stem cells, human fibroblasts, and normal mouse neural differentiation and, using proteomic analysis, found that this switch also includes the removal of SS18 and its replacement by CREST at mitotic exit. We found that switching of chromatin remodeling mechanisms is highly correlated with a broad switch in the use of neurogenic transcription factors. Knock-down of SS18 in neural stem cells causes cell-cycle exit and failure to self-renew, whereas continued expression of SS18 in neurons blocks dendritic outgrowth, underlining the importance of subunit switching. Because dominant mutations in BAF subunits underlie widely different human neurologic diseases arising in different neuronal types, our studies suggest that the characteristics of these diseases must be interpreted in the context of the different BAF assemblies in neurons rather than a singular mammalian SWItch/sucrose nonfermentable (mSWI/SNF) complex.

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    • "Although direct neuronal conversion may offer unique benefits, this approach is currently limited to a small number of protocols to specify neuronal subtypes using postnatal or adult human samples (Caiazzo et al., 2011; Liu et al., 2013; Ring et al., 2012; Son et al., 2011; Yoo et al., 2011). MiR-9/9* and miR-124 are critical components of a genetic pathway that controls the assembly of neuron-specific, ATPdependent chromatin remodeling complexes during neural development (Staahl et al., 2013; Yoo et al., 2009). In addition, these miRNAs have been shown to play key roles in the differentiation of neural progenitors to mature neurons by regulating the expression of antineural genes (Makeyev et al., 2007; Packer et al., 2008; Visvanathan et al., 2007; Xue et al., 2013). "
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