title: Early Developmental Perturbations in a Human Stem Cell Model of MODY5/HNF1B Pancreatic Hypoplasia.
abstract: Patients with an HNF1B(S148L/+) 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 HNF1B(S148L/+) 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 HNF1B(S148L/+) but not wild-type HNF1B or HNF1A. Furthermore, 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 HNF1B(S148L/+) protein. Thus, patients typically develop MODY5 but not neonatal diabetes despite exhibiting pancreatic hypoplasia.
authors.affiliation: Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Stem Cell Institute, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA; Discovery Research Division, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos #06-07, Singapore 138673, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore. Electronic address: ateo@imcb.a-star.edu.sg.
authors.forename: Adrian Kee Keong
authors.initials: AK
authors.lastname: Teo
authors.affiliation: Discovery Research Division, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos #06-07, Singapore 138673, Singapore.
authors.forename: Hwee Hui
authors.initials: HH
authors.lastname: Lau
authors.affiliation: Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Stem Cell Institute, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA.
authors.forename: Ivan Achel
authors.initials: IA
authors.lastname: Valdez
authors.affiliation: Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Stem Cell Institute, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA.
authors.forename: Ercument
authors.initials: E
authors.lastname: Dirice
authors.affiliation: Department of Pediatrics, Haukeland University Hospital, 5021 Bergen, Norway; Department of Clinical Science, KG Jebsen Center for Diabetes Research, University of Bergen, 5021 Bergen, Norway.
authors.forename: Erling
authors.initials: E
authors.lastname: Tjora
authors.affiliation: Department of Pediatrics, Haukeland University Hospital, 5021 Bergen, Norway; Department of Clinical Science, KG Jebsen Center for Diabetes Research, University of Bergen, 5021 Bergen, Norway.
authors.forename: Helge
authors.initials: H
authors.lastname: Raeder
authors.affiliation: Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Stem Cell Institute, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA. Electronic address: rohit.kulkarni@joslin.harvard.edu.
authors.forename: Rohit N
authors.initials: RN
authors.lastname: Kulkarni
mesh_terms: D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005260:Female; D051539:Hepatocyte Nuclear Factor 1-beta / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D010179:Pancreas / Q000378:metabolism / Q000473:pathology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C496495:HNF1B protein, human; D014157:Transcription Factors; D051539:Hepatocyte Nuclear Factor 1-beta