Glial cell line-derived neurotrophic factor enhances neurogenin3 gene expression and beta-cell proliferation in the developing mouse pancreas.
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.
Mwangi
Simon M
SM
Division of Digestive Diseases, Emory University, 615 Michael St., Atlanta, GA 30307, USA..
Usta
Yousef
Y
Raja
Shreya M
SM
Anitha
Mallappa
M
Chandrasekharan
Bindu
B
Parsadanian
Alexander
A
Sitaraman
Shanthi V
SV
Srinivasan
Shanthi
S
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
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
Expert Opin Ther Targets. 2008 Nov;12(11):1431-42
18851698
Development. 2002 May;129(10):2447-57
11973276
Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1607-11
10677506
J Biol Chem. 2000 Feb 4;275(5):3485-92
10652343
J Gastroenterol. 2002;37(8):583-8
12203072
Diabetes Res Clin Pract. 2006 Jul;73(1):107-10
16406191
Endocr Rev. 2007 Oct;28(6):685-705
17881611
Nat Rev Genet. 2002 Jul;3(7):524-32
12094230
Diabetes Metab Res Rev. 2003 Mar-Apr;19(2):115-23
12673779
J Surg Res. 2008 Jan;144(1):8-16
17583748
Nature. 1997 May 22;387(6631):406-9
9163426
Exp Neurol. 2004 Dec;190(2):356-72
15530875
Tissue Eng. 2006 Aug;12(8):2105-16
16968152
Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):14920-5
14657333
Nature. 1999 Aug 26;400(6747):877-81
10476967
J Clin Invest. 2001 Dec;108(11):1631-8
11733558
J Clin Invest. 2008 Jun;118(6):2316-24
18464933
Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13245-50
15340143
Nat Chem Biol. 2009 Apr;5(4):258-65
19287398
Dev Cell. 2007 Jul;13(1):103-14
17609113
Endocr Rev. 2009 May;30(3):214-27
19389995
Dev Dyn. 2008 Nov;237(11):3270-9
18924236
Endocrinology. 2009 Jan;150(1):87-97
18772243
Development. 2000 Dec;127(24):5533-40
11076772
Nat Rev Neurosci. 2002 May;3(5):383-94
11988777
Genes Dev. 1998 Jun 15;12(12):1763-8
9637677
Diabetes. 2000 Feb;49(2):163-76
10868931
Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1865-70
17267606
Neuroscience. 2006 Nov 17;143(1):241-51
16996218
Gastroenterology. 2008 Mar;134(3):727-37
18241861
Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):7018-23
9192684
Nature. 2000 Dec 14;408(6814):864-8
11130726
Genes Dev. 1997 Jul 1;11(13):1662-73
9224716
Development. 2000 Aug;127(16):3533-42
10903178
Diabetologia. 2004 Apr;47(4):597-613
15298336
Diabetologia. 2007 Jul;50(7):1463-71
17476475
Diabetes. 2003 Jan;52(1):102-10
12502499