Early Developmental Perturbations in a Human Stem Cell Model of MODY5/HNF1B Pancreatic Hypoplasia

Abstract

SummaryPatients 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.

The molecular functions of hepatocyte nuclear factors – In and beyond the liver

“…In this respect, human induced pluripotent stem cell models, especially those that are derived from patients, are a promising tool for the analysis of human-specific disease mechanisms during the development of different tissues. 161,162 Though many HNF proteins and their isoforms share a high degree of homology, they may play both interdependent as well as distinct roles depending on their expression levels and the tissue(s) involved. The complexity is reflected in the cross-regulatory circuits formed by the HNF proteins that specify tissue identity and function.…”

Dynamic proteome profiling of human pluripotent stem cell-derived pancreatic progenitors

“…To describe the proteome dynamics during early stages of pancreatic differentiation, we used a serum‐free differentiation protocol to produce definitive endoderm, foregut endoderm and pancreatic progenitor cells (Figure ). IF confirmed NANOG+ cells in hiPSCs (day 0), SOX17, and CXCR4 expression in definitive endoderm cells (day 5), HNF1β+ cells in foregut endoderm (day 12), and positive staining for PDX1 in pancreatic progenitors at day 17 of the differentiation protocol (Supplementary Figure S1A,B).…”

Novel GLI3 variant causing overlapped Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS) phenotype with agenesis of gallbladder and pancreas

“…Such sophisticated spatial and sequential SHH signaling is essential for proper organ development from these endodermal buds. Because we have not done comprehensive genomics study, possibility of coincidental additional pathogenic variants in Pdx1, Ptf1a, Gata4 and Gata6, known to be associated with agenesis of pancreas [23], cannot be excluded in this case. Although it remains unclear why agenesis of the gallbladder and the pancreas is uncommon in GLI3 morphopathy, a slight difference in the gradient or the balance between activator and repressor induced by a slight difference of protein tertiary structure may contribute to the apparent phenotypic difference in GLI morphopathy.…”