The concerted activities of Pax4 and Nkx2.2 are essential to initiate pancreatic β-cell differentiation

Pancreatic β cells play a central role in maintaining glucose homeostasis because they secrete insulin in response to increased level of blood glucose; failure of this capacity constitutes a major component of the pathogenesis of diabetes. The identification of key regulators of pancreatic β-cell di...

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Bibliographic Details
Published in:Developmental biology 2004-02, Vol.266 (1), p.178-189
Main Authors: Wang, Junfeng, Elghazi, Lynda, Parker, Susan E, Kizilocak, Hasan, Asano, Masahide, Sussel, Lori, Sosa-Pineda, Beatriz
Format: Article
Language:English
Subjects:
Animals
Cell Differentiation - physiology
Homeodomain Proteins - genetics
Homeodomain Proteins - physiology
Immunohistochemistry
In Situ Hybridization
Islets of Langerhans - cytology
Islets of Langerhans - embryology
Mice
Mice, Knockout
Mouse
Nkx2.2
Nkx2.2 protein
Paired Box Transcription Factors
Pancreas
Pax4
Pax4 protein
Pax6
Pdx1 protein
Transcription Factors - genetics
Transcription Factors - physiology
β-cell differentiation
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Summary:Pancreatic β cells play a central role in maintaining glucose homeostasis because they secrete insulin in response to increased level of blood glucose; failure of this capacity constitutes a major component of the pathogenesis of diabetes. The identification of key regulators of pancreatic β-cell differentiation is relevant for the overall understanding of this process and for future experiments aimed at regenerating insulin-producing β cells from pancreatic or embryonic stem cells. Several studies using transgenic or knockout mice have established that the development and function of pancreatic β cells are controlled by several genes encoding specific transcription factors. By inactivating the homeobox gene Pax4, we previously demonstrated that its function is required for the formation of mature insulin-producing cells. Here, we show that during pancreas ontogeny, Pax4 is expressed in differentiating endocrine cells, including β cells. Pax4 activity appears essential for appropriate initiation of β-cell differentiation because loss of Pax4 prevents the expression of Pdx1, HB9 and insulin in β-cell precursors. This role of Pax4 appears to be accomplished via its genetic interaction with another homeobox gene, Nkx2.2.
ISSN:0012-1606
1095-564X
DOI:10.1016/j.ydbio.2003.10.018