UC San Diego
The Role of UPF3B in Pluripotency and Differentiation
- Author(s): Shao, Ada Le
- Advisor(s): Wilkinson, Miles F
- et al.
The Nonsense-Mediated RNA Decay (NMD) pathway prevents the accumulation of potentially toxic proteins in the cell by targeting aberrant RNA transcripts with premature termination codons (PTCs) for decay. While originally for its RNA surveillance capacity, NMD was more recently discovered to target not only aberrant RNA transcripts but also normal, wild-type transcripts, regulating 5-20% of the normal transcriptome. This, in turn, has led to the hypothesis that NMD, by fine-tuning gene expression, functions in orchestrating biological processes such as development.
Recent studies have identified mutations in the NMD factor gene, UPF3B, as the cause of syndromic and non-syndromic intellectual disability in human patients; these patients also frequently suffer from psychiatric and neurodevelopmental disorders, including schizophrenia, autism, and attention-deficit disorder. The role of NMD in neurodevelopment was further supported by work from our laboratory identifying the function of miR-128 mediated repression of NMD in neural differentiation.
For these reasons, I elected to study the role of the NMD factor UPF3B and microRNA regulation of NMD in neurodevelopment. In summary, I have identified a microRNA regulatory circuit in which the neurally enriched microRNAs, miR-132 and miR-9/-124/-128, repress the UPF2 and UPF3B branches of NMD, respectively. To examine the role of the UPF3B branch of NMD in neurodevelopment, I derived iPSCs and NPCs from patients with UPF3B-null mutations. Using these UPF3B-deficient iPSCs and NPCs, I obtained substantial evidence that UPF3B promotes pluripotency, while depletion or absence of UPF3B promotes differentiation.