PRDM16 functions as a co-repressor in the BMP pathway to suppress neural stem cell proliferation

• BMP signalling acts as an instructive cue in multiple developmental processes such as tissue patterning, stem cell proliferation and differentiation. It remains unclear how the same signalling input can be translated into a diverse range of cell-specific outputs. Here we have identified PRDM16 as a key regulator for BMP-induced neural stem cell (NSC) quiescence. We have determined genomic distribution of the SMAD4/pSMAD complexes in quiescent and proliferating NSCs and find that PRDM16 tethers the SMAD4 and pSMAD1/5/8 proteins at their co-bound genomic sites to prevent transcriptional activation of cell proliferation genes. Loss of Prdm16 led to relocation of the SMAD complex to neighbouring genomic regions, leading to aberrant upregulation of BMP target genes. Such function of PRDM16 is also required for the specification of choroid plexus (ChP) epithelial cells. Using a single-cell resolution fluorescent in situapproach, we show that a SMAD/PRDM16 co-repressed gene, Wnt7b, and Wnt activity become upregulated in the Prdm16 mutant ChP, which correlates with abnormally elevated cell proliferation. Together, our work defines the mechanism by which SMAD4 and pSMAD1/5/8 repress gene expression during the induction of cell quiescence and suggests a regulatory circuit composed of BMP and Wnt signaling and PRDM16 in the control of stem cell behaviors.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

NATURVETENSKAP  -- Biologi -- Utvecklingsbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Developmental Biology (hsv//eng)

Nyckelord

Molecular Biology

molekylärbiologi

utvecklingsbiologi

Developmental Biology

Developmental Neurosciences

medicinsk utvecklings- och neurobiologi

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