title: Glial cell line-derived neurotrophic factor enhances neurogenin3 gene expression and beta-cell proliferation in the developing mouse pancreas.
abstract: 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 beta-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 beta-cell development, as well as on beta-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/beta(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 beta-cell mass at embryonic day 18 (E18), as well as higher beta-cell proliferation and Pdx1 expression in beta-cells at E18 and postnatal day 1. In the HIT-T15 beta-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 beta-cell line demonstrated that GDNF can influence Pdx1 gene expression by enhancing the binding of Sox9 and neuroD1/beta(2) to the Pdx1 promoter. Our data provide evidence of a mechanism by which GDNF influences beta-cell development. GDNF could be a potential therapeutic target for the treatment and prevention of diabetes.
authors.affiliation: Division of Digestive Diseases, Emory University, 615 Michael St., Atlanta, GA 30307, USA..
authors.forename: Simon M
authors.initials: SM
authors.lastname: Mwangi
authors.forename: Yousef
authors.initials: Y
authors.lastname: Usta
authors.forename: Shreya M
authors.initials: SM
authors.lastname: Raja
authors.forename: Mallappa
authors.initials: M
authors.lastname: Anitha
authors.forename: Bindu
authors.initials: B
authors.lastname: Chandrasekharan
authors.forename: Alexander
authors.initials: A
authors.lastname: Parsadanian
authors.forename: Shanthi V
authors.initials: SV
authors.lastname: Sitaraman
authors.forename: Shanthi
authors.initials: S
authors.lastname: Srinivasan
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D002460:Cell Line; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D006224:Cricetinae; D005136:Eye Proteins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005865:Gestational Age; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D038081:Organogenesis; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism; D010179:Pancreas / Q000196:embryology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D000072056:Transcription Factor HES-1; D015533:Transcriptional Activation; D014162:Transfection; D015854:Up-Regulation
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005136:Eye Proteins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D012097:Repressor Proteins; D055758:SOX9 Transcription Factor; D015534:Trans-Activators; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse; C407737:Neurog3 protein, mouse; C110218:Pax4 protein, mouse; C000605732:Pax6 protein, mouse; C000605733:Pax6 protein, rat; C084010:pancreatic and duodenal homeobox 1 protein; C093564:Neurogenic differentiation factor 1
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