Non-neural tyrosine hydroxylase, via modulation of endocrine pancreatic precursors, is required for normal development of beta cells in the mouse pancreas

Abstract

Aims/hypothesis: Apart from transcription factors, little is known about the molecules that modulate the proliferation and differentiation of pancreatic endocrine cells. The early expression of tyrosine hydroxylase (TH) in a subset of glucagon+ cells led us to investigate whether catecholamines have a role in beta cell development. Methods: We studied the immunohistochemical characteristics of TH-expressing cells in wild-type (Th+/+) mice during early pancreas development, and analysed the endocrine pancreas phenotype of TH-deficient (Th−/−) mice. We also studied the effect of dopamine addition and TH-inhibition on insulin-producing cells in explant cultures. Conclusions/interpretation: A non-neural catecholaminergic pathway appears to modulate the pancreatic endocrine precursor and insulin producing cell neogenesis. This finding may have important implications for approaches seeking to promote the generation of beta cells to treat diabetes. Results: In the mouse pancreas at embryonic day (E)12.5–E13.5, the ∼10% of early glucagon+ cells that co-expressed TH rarely proliferated and did not express the precursor marker neurogenin 3 at E13.5. The number of insulin+ cells in the Th−/− embryonic pancreas was decreased as compared with wild-type embryos at E13.5. While no changes in pancreatic and duodenal homeobox 1 (PDX1)+-progenitor cell number were observed between groups at E12.5, the number of neurogenin 3 and NK2 homeobox 2 (NKX2.2)-expressing cells was reduced in Th−/− embryonic pancreas, an effect that occurred in parallel with increased expression of the transcriptional repressor Hes1. The potential role of dopamine as a pro-beta cell stimulus was tested by treating pancreas explants with this catecholamine, which resulted in an increase in total insulin content and insulin+ cells relative to control explants.