Protein arginine methylation in the control of neural stem cell ‘stemness’ and differentiation

During development, cortical neuroepithelial stem cells (NSCs) generate all the neurons and glia of the central nervous system in a precise spatiotemporal manner. Aberrations of this process are linked to neurological conditions, such as autism and schizophrenia. The molecular mechanisms controlling NSCs’ transition from ‘stemness’ to differentiation remain elusive. We recently identified a novel regulatory complex, comprised of PRDM4 protein and the protein arginine methyltransferase 5 (PRMT5), whose activity maintains NSC ‘stemness’ in vitro. 

We hypothesise that PRDM4/PRMT5-mediated protein arginine methylation (R-Me) is necessary to maintain NSC ‘stemness’. We have generated mice with the cortical NSC-specific deletion of PRDM4 and analysed changes in R-Me in these mice. We will investigate outcomes of the observed reduction in R-Me and validate the strongest candidate of the proteomic screen. We will characterise differentiation profiles of NSCs from the mutant mice and biochemically characterise PRDM4:PRMT5-mediated KSRP-R-Me in vivo and in vitro.

Our findings will validate a novel mechanism of NSC ‘stemness’ control, mediated by protein R-Me, providing the basis for further investigations into its role in NSC reprogramming and neurological diseases.