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

Junfeng Wang; Lynda Elghazi; Susan E. Parker; Hasan Kizilocak; Masahide Asano; Lori Sussel; Beatriz Sosa-Pineda

doi:10.1016/j.ydbio.2003.10.018

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

Junfeng Wang, Lynda Elghazi, Susan E. Parker, Hasan Kizilocak, Masahide Asano, Lori Sussel, Beatriz Sosa-Pineda^*

^*Corresponding author for this work

Medicine, Nephrology Division

Research output: Contribution to journal › Article › peer-review

141 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	178-189
Number of pages	12
Journal	Developmental Biology
Volume	266
Issue number	1
DOIs	https://doi.org/10.1016/j.ydbio.2003.10.018
State	Published - Feb 1 2004

Funding

We thank S. Kalloway and S. Holloway for excellent technical assistance, A. Demirkan for help with immunohistochemistry, G. Oliver for critical reading of this manuscript, K.G. Murti and K. Barnes for help with confocal laser-scanning microscopy, and A. McArthur for editing the manuscript. We also thank the following people for generously providing reagents: M. German, P. Gruss, T. Jessell, J. Kehrl, D. Mastick, P. Serup, and C.V. Wright. This work was supported in part by grant VUMC9183 (B.S.-P.) from the Beta Cell Biology Consortium (Vanderbilt University, Nashville, TN), by Cancer Center Support CA 21765 from the National Cancer Institute, and by the American Lebanese Syrian Associated Charities (ALSAC).

Keywords

Mouse
Nkx2.2
Pancreas
Pax4
Pax6
β-cell differentiation

ASJC Scopus subject areas

Molecular Biology
Cell Biology
Developmental Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ydbio.2003.10.018

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

abstract = "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.",

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note = "Funding Information: We thank S. Kalloway and S. Holloway for excellent technical assistance, A. Demirkan for help with immunohistochemistry, G. Oliver for critical reading of this manuscript, K.G. Murti and K. Barnes for help with confocal laser-scanning microscopy, and A. McArthur for editing the manuscript. We also thank the following people for generously providing reagents: M. German, P. Gruss, T. Jessell, J. Kehrl, D. Mastick, P. Serup, and C.V. Wright. This work was supported in part by grant VUMC9183 (B.S.-P.) from the Beta Cell Biology Consortium (Vanderbilt University, Nashville, TN), by Cancer Center Support CA 21765 from the National Cancer Institute, and by the American Lebanese Syrian Associated Charities (ALSAC).",

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AU - Asano, Masahide

AU - Sussel, Lori

AU - Sosa-Pineda, Beatriz

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N2 - 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.

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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