Role of RNA regulation in neuronal differentiation and development
My laboratory’s primary research interests lie in understanding molecular mechanisms underlying development. We are currently addressing such questions in both neural and germ cell development, including stem cell establishment, stem cell self-renewal, and cell fate commitment. Our projects on the nervous system primarily revolve around “nonsense-mediated decay (NMD),” a RNA degradation pathway that rapidly degrades subsets of transcripts in a developmentally regulated fashion (Chang et al. Ann Rev Biochem 75:51). We have focused our recent efforts on understanding NMD’s role in regulating neural development and function, based on two fundamental discoveries. First, loss of a specific branch of NMD that we have been studying for several years—the UPF3B-dependent branch—causes intellectual disability in humans. Many UPF3B patients also suffer from autism and/or schizophrenia, suggesting a role for NMD in these neuro-developmental disorders, as well. Second, my laboratory and others discovered that NMD is not just an RNA surveillance pathway that degrades aberrant mRNAs, but it is also a RNA decay pathway that degrades subsets of normal mRNAs. My laboratory has followed up on these discoveries by (i) generating a mouse model for UPF3B deficiency (these mice have behavioral defects mimicking those in humans), (ii) generating mice lacking the Upf3b paralog—Upf3a—which unexpectedly have hyper NMD, and (iii) examining the role of NMD and its mRNA targets in neural differentiation in both human and mouse cell lines (our recent publications on this topic include Bruno et al. Mol Cell 2011 and Lou et al. Cell Reports 2014).
Chang, Y.-F., Imam, J.S. & Wilkinson, M.F. (2007) “The Nonsense-Mediated Decay RNA Surveillance Pathway,” Annual Review of Biochemistry, Ed.: Kornberg, R., Annual Reviews Inc.
Bruno I.G., Karam R., Huang L., Bhardwaj A., Lou C.-H., Shum E.Y., Song H-W., Corbett M.A., Gifford W.D., Gecz J., Phaff S. & Wilkinson M.F. Identification of a MicroRNA that Activates Gene Expression by Repressing Nonsense-Mediated RNA Decay. Molecular Cell 42:500-510 (2011).
Karam R. & Wilkinson MF. A Conserved MicroRNA/NMD Regulatory Circuit Controls Gene Expression. RNA Biology 9:22-26 (2012).
Nguyen LS, Jolly L, Shoubridge C, Chan WK, Huang L, Laumonnier F, Raynaud M, Hackett A, Field M, Rodriguez J, Srivastava AK, Lee Y, Long R, Addington AM, Rapoport JL, Suren S, Hahn CN, Gamble J, Wilkinson MF, Corbett MA, Gecz J. Transcriptome profiling of UPF3B/NMD-deficient lymphoblastoid cells from patients with various forms of intellectual disability. Mol Psychiatry 17:1103-15 (2012).
Huang L & Wilkinson MF. Regulation of Nonsense-Mediated RNA Decay. WIRES RNA 3: 807-828 (2012).
Karam R, Wengrod J, Gardner LB, Wilkinson MF. Regulation of Nonsense-Mediated mRNA Decay: Implications for Physiology and Disease. Biochim Biophys Acta 1829:624-33 (2013).
Nguyen LS, Wilkinson MF & Gecz J. Nonsense-Mediated mRNA Decay: Inter-Individual Variability and Human Disease. Neuroscience and Biobehavioral Reviews 2013 Nov 14. pii: S0149-7634(13)00270-4. doi: 10.1016/j.neubiorev.2013.10.016. [Epub ahead of print].
Liu C, Karam R, Zhou Y, Su F, Ji Y, Li G, Xu G, Lu L, Wang C, Song M, Zhu J, Wang Y, Zhao Y, Foo WC, Zuo M, Valasek MA, Javle M, Wilkinson MF*, Lu Y.* The UPF1 RNA Surveillance Gene is Commonly Mutated in Pancreatic Adenosquamous Carcinoma. Nature Medicine 20:596-8 (2014). *co-corresponding authors
Lou C-H, Shao A, Shum EY, Espinoza JL, Huang L, Karam R & Wilkinson MF. Posttranscriptional Control of the Stem and Neurogenic Programs by the Nonsense-Mediated RNA Decay Pathway. Cell Reports 6:748-64 (2014).
Karam R, Lou C-H, Kroeger H, Huang L, Lin JH, Wilkinson MF. The Unfolded Response is Shaped by the NMD Pathway. EMBO Reports (in press).