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SOX9 regulates endocrine cell differentiation during human fetal pancreas development.
- Source :
-
The international journal of biochemistry & cell biology [Int J Biochem Cell Biol] 2012 Jan; Vol. 44 (1), pp. 72-83. Date of Electronic Publication: 2011 Sep 29. - Publication Year :
- 2012
-
Abstract
- The transition of pancreatic progenitor cells to mature endocrine cells is regulated by the sequential activation and interaction of several transcription factors. In mice, the transcription factor Sox9 has been shown to support endocrine cell differentiation. However, the functional role of SOX9 during pancreas development in the human has yet to be determined. The present study was to characterize SOX9 expression during human fetal pancreas development and examine its functional role by transfection with SOX9 siRNA or SOX9 expression vectors. Here we report that SOX9 was most frequently expressed in PDX1(+) cells (60-83%) and least in mature endocrine cells (<1-14%). The proliferation of SOX9(+) cells was significantly higher at 8-10 weeks than at 14-21 weeks (p<0.05) or 20-21 weeks (p<0.01). SOX9 frequently co-localized with FOXA2, NGN3 and transcription factors linked to NGN3 (NKX2.2, NKX6.1, PAX6). siRNA knockdown of SOX9 significantly decreased islet-epithelial cell proliferation, NGN3, NKX6.1, PAX6 and INS mRNA levels and the number of NGN3(+) and insulin(+) cells (p<0.05) while increasing GCG mRNA and glucagon(+) cells (p<0.05). Examination of SOX9 associated signaling pathways revealed a decrease in phospho-Akt (p<0.01), phospho-GSK3β (p<0.01) and cyclin D1 (p<0.01) with a decrease in nuclear β-catenin(+) (p<0.05) cells following SOX9 siRNA knockdown. In contrast, over-expression of SOX9 significantly increased the number of islet cells proliferating, NGN3, NKX6.1, PAX6 and INS mRNA levels, the phospho-Akt/GSK3β cascade and the number of insulin(+) cells. Our results demonstrated that SOX9 is important for the expression of NGN3 and molecular markers of endocrine cell differentiation in the human fetal pancreas.<br /> (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Subjects :
- Basic Helix-Loop-Helix Transcription Factors metabolism
Cell Differentiation physiology
Gene Expression Regulation, Developmental
Gene Knockdown Techniques
Glycogen Synthase Kinase 3 metabolism
Glycogen Synthase Kinase 3 beta
Homeobox Protein Nkx-2.2
Homeodomain Proteins
Humans
Islets of Langerhans cytology
Islets of Langerhans metabolism
Nerve Tissue Proteins metabolism
Nuclear Proteins
Oncogene Protein v-akt metabolism
Pancreas cytology
RNA, Messenger biosynthesis
RNA, Messenger genetics
SOX9 Transcription Factor genetics
SOX9 Transcription Factor metabolism
Signal Transduction
Transcription Factors
Transfection
Islets of Langerhans embryology
Pancreas embryology
SOX9 Transcription Factor biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1878-5875
- Volume :
- 44
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- The international journal of biochemistry & cell biology
- Publication Type :
- Academic Journal
- Accession number :
- 21983268
- Full Text :
- https://doi.org/10.1016/j.biocel.2011.09.008