Early developmental perturbations in a human stem cell model of MODY5/HNF1B pancreatic hypoplasia

Early developmental perturbations in a human stem cell model of MODY5/HNF1B pancreatic hypoplasia
Title:
Early developmental perturbations in a human stem cell model of MODY5/HNF1B pancreatic hypoplasia
Other Titles:
Stem Cell Reports
Keywords:
Publication Date:
11 February 2016
Citation:
Early Developmental Perturbations in a Human Stem Cell Model of MODY5/HNF1B Pancreatic Hypoplasia Teo, Adrian Kee Keong et al. Stem Cell Reports, Volume 6, Issue 3, 357 - 367
Abstract:
Patients with an 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. 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 HNF1BS148L/+ protein. Thus, patients typically develop MODY5 but not neonatal diabetes despite exhibiting pancreatic hypoplasia.
License type:
http://creativecommons.org/licenses/by-nc-nd/4.0/
Funding Info:
The hiPSC lines used were derived with support from the Joslin DRC iPS Core Facility ( NIH 5 P30 DK036836-27 ). FACS analysis was supported by the HSCI/DRC Flow Core (NIH P30DK036836 ). Microarray studies were performed by the Molecular Genetics Core Facility at Children's Hospital Boston, supported by NIH- P50-NS40828 and NIH- P30-HD18655 . We thank B. Wagner for assistance with microarray analyses; and K. Tomita, E.K. Tan, N.R. Dunn, Y.-H. Zhou, and Y.-I. Chi for providing plasmids. A.K.K.T. was supported by a Juvenile Diabetes Research Foundation (JDRF) Postdoctoral Fellowship and is currently supported by the Institute of Molecular and Cell Biology (IMCB), A∗STAR , NHG-KTPH SIG/14033 , the NUHS-CG Metabolic In-Vitro Core Seed Funding , and the JCO Career Development Award (CDA) 15302FG148 , A∗STAR. I.A.V. is supported by an HSCI Sternlicht Director's Fund Award and a NIH F31DK098931 award. E.D. is supported by an Advanced JDRF Postdoctoral Fellowship . H.R. is supported by grants from Bergen Forskningsstiftelse (BFS), the Western Norway Regional Health Authority and the Novo Nordisk Foundation . R.N.K. is supported by the HSCI , NIH grants RO1 DK 67536 , RO1 DK 055523 , and R01103215 , and a grant from AstraZeneca .
Description:
ISSN:
2213-6711
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