Adrian Kee Keong Teo1,2,3,4,5*, Hwee Hui Lau2, Ivan Achel Valdez1, Ercument Dirice1, Erling Tjora6,7, Helge Raeder6,7, Rohit N. Kulkarni1*
1 Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts 02215, USA
2 Discovery Research Division, Institute of Molecular and Cell Biology, Proteos, Singapore 138673, Singapore
3 School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore
4 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596, Singapore
5 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore
6 Department of Pediatrics, Haukeland University Hospital, 5021 Bergen, Norway
7 KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway
Published in Stem Cell Reports on 11 Feb 2016.
Patients with a HNF1BS148L/+ mutation (MODY5) typically exhibit pancreatic hypoplasia. However, the molecular mechanisms are unknown due to inaccessibility of patient material and because mouse models do not fully recapitulate MODY5. Here we differentiated MODY5-human induced pluripotent stem cells (hiPSCs) into pancreatic progenitors and show that the HNF1BS148L/+ mutation causes a compensatory increase in several pancreatic transcription factors, and surprisingly, a decrease in PAX6 pancreatic gene expression. The lack of suppression of PDX1, PTF1A, GATA4 and GATA6 indicates that MODY5-mediated pancreatic hypoplasia is mechanistically-independent. Overexpression studies demonstrate that a compensatory increase in PDX1 gene expression is due to mutant HNF1BS148L/+ but not wild-type HNF1B or HNF1A. Further, HNF1B does not appear to directly regulate PAX6 gene expression necessary for glucose tolerance. Our results demonstrate compensatory mechanisms in the pancreatic transcription factor network due to mutant HNF1BS148L/+ protein. Thus, patients typically develop MODY5 but not neonatal diabetes despite exhibiting pancreatic hypoplasia.
Figure LEGEND: Transcriptional changes in MODY5 pancreatic cells
Model depicting the impact of mutant HNF1BS148L/+ on early human pancreas development. Mutant HNF1BS148L/+ evokes an early increase in definitive endoderm genes followed by a subsequent increase in pancreas-related foregut endoderm genes. Thus although MODY5 patients typically develop pancreatic hypoplasia, there is a low occurrence of neonatal diabetes. The decrease in early PAX6 gene expression in pancreatic progenitors may partly account for the subsequent β cell dysfunction in MODY5 patients.
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