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Open Access Publications from the University of California

Role of UPF3B in Neurodevelopment

  • Author(s): Higgins, Kendall Todd
  • Advisor(s): Wilkinson, Miles
  • et al.

The Nonsense Mediated Decay (NMD) pathway was originally discovered for its role in degrading mRNA transcripts bearing a premature termination codon (PTC). Recently, it has been shown that the NMD pathway also degrades a subset of normal transcripts. This raises the possibility that NMD regulates normal biological events, including development. Indeed, increasing evidence suggests that NMD regulates various developmental events, including governing early cell fate in the specification of the three germ layers: endoderm, mesoderm, and ectoderm, from the pluripotent stem cell. In particular, NMD promotes formation of mesoderm while inhibiting the formation of endoderm.

As support of NMD holding developmental importance, to date 11 patients bearing mutations in one NMD factor, UPF3B, have been reported, all of which exhibit neurodevelopmental disorders including intellectual disability, autism spectrum disorder, and schizophrenia. In addition, reports of individuals with copy number variants in NMD factors UPF2, UPF3A, RBM8A, EIF4A3, RNPS1, and SMG6, have been shown to be associated with neurodevelopmental disorders. This evidence suggests a role for NMD in governing neurodevelopment. Using both in vitro and in silico methods, I have elected to identify the role of one such NMD factor, UPF3B in early cell fate. Specifically, focusing on its regulation of the neural induction process from the pluripotent stem cell state. As well as providing speculation on a potential evolutionary significance of the NMD pathway and its implications in neurodevelopment in the transition from early hominid to modern human.

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