Cross-Regulation between an Alternative Splicing Activator and a Transcription Repressor Controls Neurogenesis

SummaryNeurogenesis requires the concerted action of numerous genes that are regulated at multiple levels. However, how different layers of gene regulation are coordinated to promote neurogenesis is not well understood. We show that the neural-specific Ser/Arg repeat-related protein of 100 kDa (nSR100/SRRM4) negatively regulates REST (NRSF), a transcriptional repressor of genes required for neurogenesis. nSR100 directly promotes alternative splicing of REST transcripts to produce a REST isoform (REST4) with greatly reduced repressive activity, thereby activating expression of REST targets in neural cells. Conversely, REST directly represses nSR100 in nonneural cells to prevent the activation of neural-specific splicing events. Consistent with a critical role for nSR100 in the inhibition of REST activity, blocking nSR100 expression in the developing mouse brain impairs neurogenesis. Our results thus reveal a fundamental role for direct regulatory interactions between a splicing activator and transcription repressor in the control of the multilayered regulatory programs required for neurogenesis.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (273 K)Download as PowerPoint slideHighlights► nSR100 negatively regulates the REST transcriptional repressor during neurogenesis ► nSR100 represses REST via activation of a neural-specific splicing switch ► REST directly represses nSR100 expression in nonneural cells ► Loss of nSR100 promotes REST-mediated repression of neurogenesis