Glial cell line-derived neurotrophic factor enhances neurogenin3 gene expression and -cell proliferation in the developing mouse pancreas

Mwangi SM, Usta Y, Raja SM, Anitha M, Chandrasekharan B, Parsadanian A, Sitaraman SV, Srinivasan S. Glial cell line-derived neurotrophic factor enhances neurogenin3 gene expression and -cell proliferation in the developing mouse pancreas. Am J Physiol Gastrointest Liver Physiol 299: G283–G292, 2010. First published May 6, 2010; doi:10.1152/ajpgi.00096.2010.—Glial cell line-derived neurotrophic factor (GDNF) is a factor produced by glial cells that is required for the development of the enteric nervous system. In transgenic mice that overexpress GDNF in the pancreas, GDNF has been shown to enhance -cell mass and improve glucose control, but the transcriptional and cellular processes involved are not known. In this study we examined the influence of GDNF on the expression of neurogenin3 (Ngn3) and other transcription factors implicated in early -cell development, as well as on -cell proliferation during embryonic and early postnatal mouse pancreas development. Embryonic day 15.5 (E15.5) mouse pancreatic tissue when exposed to GDNF for 24 h showed higher Ngn3, pancreatic and duodenal homeobox gene 1 (Pdx1), neuroD1/ 2, paired homeobox gene 4 (Pax4), and insulin mRNA expression than tissue exposed to vehicle only. Transgenic expression of GDNF in mouse pancreata was associated with increased numbers of Ngn3-expressing pancreatic cells and higher -cell mass at embryonic day 18 (E18), as well as higher -cell proliferation and Pdx1 expression in -cells at E18 and postnatal day 1. In the HIT-T15 -cell line, GDNF enhanced the expression of Pax6. This response was, however, blocked in the presence of Pdx1 small interfering RNA (siRNA). Chromatin immunoprecipitation studies using the HIT-T15 -cell line demonstrated that GDNF can influence Pdx1 gene expression by enhancing the binding of Sox9 and neuroD1/ 2 to the Pdx1 promoter. Our data provide evidence of a mechanism by which GDNF influences -cell development. GDNF could be a potential therapeutic target for the treatment and prevention of diabetes.