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dc.contributor.authorAlpagu, Yunus
dc.identifier.citationAlpagu, Y. (2018). Modelling Mitchell-Riley Syndrome in vitro using iPS cells derived from RFX6 mutant patient. Doctoral thesis, Nanyang Technological University, Singapore.
dc.description.abstractThe forkhead transcription factor Regulatory Factor X, 6 (RFX6) is essential for the development of the mammalian pancreas. In humans, RFX6 mutations are responsible for Mitchell-Riley Syndrome (MRS), which is characterized by neonatal diabetes with pancreatic hypoplasia. Similarly, Rfx6 mutant mice fail to develop all islet endocrine cell types and die soon after birth. Although RFX6 mutations yield a dramatic disease phenotype, our knowledge about RFX6 function and regulation is extremely limited. To address this deficit, we have generated human induced pluripotent cell (hiPSC) lines from a Syrian MRS patient with a novel RFX6 null mutation. Based on published, but limited work in the mouse, our expectation was that RFX6 functions specifically at the transition between NGN3+ pancreatic endocrine progenitors to mature hormone-containing islet subtypes. Our data, however, show that (1) during directed differentiation toward the pancreatic lineage, RFX6 expression precedes the activation of the master regulator gene PDX1, with weak RFX6 expression first detected as early as day 4; (2) MRS iPSC fail to robustly activate the pan-endodermal organ marker SOX9 as well as PDX1; and (3) wild-type H9 human ES cells (hESC) routinely produce >80% PDX1+;NKX6-1+ pancreatic progenitors by day 12 of differentiation, whilst MRS iPSC consistently yield <30%. Taken together, loss of RFX6 restricts formation of pancreatic progenitors. We propose that RFX6 plays a previously unanticipated, earlier role in human pancreatic development as an activator and/or repressor. Lastly, both humans and mice display developmental defects in the gall bladder and duodenum, suggesting that RFX6 function is not limited to the pancreatic lineage.en_US
dc.format.extent168 p.en_US
dc.subjectDRNTU::Science::Biological sciencesen_US
dc.titleModelling Mitchell-Riley Syndrome in vitro using iPS cells derived from RFX6 mutant patienten_US
dc.contributor.supervisorRay Dunn
dc.contributor.supervisorAlbert I. Chenen_US
dc.contributor.schoolSchool of Biological Sciencesen_US​Doctor of Philosophy (SBS)en_US
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