Cell development and islet function

Abstract

How organs are formed during embryonic development is a fundamental problem in biology but it also has profound implications for human disease. Thus, many diseases originate as a consequence of failures during embryonic development. Also, aberrant reactivation of embryonic genetic programs in adult cells contribute to multiple pathologies, including pancreatitis, cancer, and diabetes. More recently, our advance in the understanding of the molecular embryonic pathways has proven very useful to develop strategies to generate in vitro cells of interest from pluripotent stem cells. Also, aberrant reactivation of embryonic genetic programs contributes to several pancreatic pathologies including pancreatitis, cancer and diabetes.

Our understanding of the transcriptional network regulating the formation of pancreas, and more specifically insulin-producing beta cells, have increased enormously during the last decade. Among the key transcription factors involved in pancreas formation, two members of the GATA zinc finger transcription factor family, GATA4 and GATA6, have been identified. Interestingly, an association between GATA6 and GATA4 mutations and human congenital pancreas agenesis has been reported. Using conditional knockout mouse models, our group have described the potential mechanisms underlying pancreatic agenesis in humans with GATA mutations. We have found that GATA4 and GATA6 are involved in various stages of pancreas formation, including proliferation and differentiation of the pancreatic progenitor cells. Moreover, GATA factors are also required for proper adult beta cell function. Thus, loss of GATA6 in beta cells leads to glucose intolerance and defects in insulin biosynthesis and secretion in mice. Future studies will determine whether deficiency in GATA factors might play a more general role in beta cell dysfunction in diabetes mellitus in humans.