Abstract
Aims/hypothesisApart 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.MethodsWe 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.ResultsIn 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.Conclusions/interpretationA 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-014-3341-6) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Highlights
Studies of developmental biology have led to significant advances in our understanding of the generation of insulinproducing cells [1, 2]
tyrosine hydroxylase (TH) is expressed in a subset of early glucagon+ cells in the developing mouse pancreas We first sought to better characterise the early TH-expressing cell population
Pancreatic Th mRNA was analysed in samples from E11.5 to E15.5, the latter being the embryonic stage during which significant sympathetic fibre innervation begins
Summary
Studies of developmental biology have led to significant advances in our understanding of the generation of insulinproducing cells [1, 2]. Diabetologia (2014) 57:2339–2347 the pool of pancreatic progenitor cells and lead to a mature beta cell phenotype. These molecules include specific combinations of well-characterised transcription factors [3, 4] and less well known secreted signals [5,6,7]. The secondary transition, from E13.5 to E15.5, involves massive differentiation of beta cells and continued expansion and branching [11]. The initial stages of foregut endoderm pancreatic specification and epithelial expansion are strongly influenced by signals from neighbouring tissues, including the mesenchyme [5, 11, 12]. Growth factors known to influence early pancreatic cell decisions include fibroblast growth factors, Wnt and TGFβ family members [5, 6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
