Tbx1 regulates oral epithelial adhesion and palatal development (original) (raw)

Journal Article

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1

Human Gene Sciences Center

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Tokyo Medical and Dental University

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1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510

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Japan

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2

Department of Molecular Biology

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1

Human Gene Sciences Center

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Tokyo Medical and Dental University

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1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510

,

Japan

,

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2

Department of Molecular Biology

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3

Department of Pathology

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University of Texas Southwestern Medical Center

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5323 Harry Hines Blvd., Dallas, TX 75390-9148

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USA

and

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4

Gladstone Institute of Cardiovascular Disease and Department of Pediatrics

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University of California

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1650 Owens Street, San Francisco, CA 94158

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USA

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Department of Molecular Biology

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Received:

27 December 2011

Revision received:

31 January 2012

Accepted:

21 February 2012

Published:

27 February 2012

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Noriko Funato, Masataka Nakamura, James A. Richardson, Deepak Srivastava, Hiromi Yanagisawa, Tbx1 regulates oral epithelial adhesion and palatal development, Human Molecular Genetics, Volume 21, Issue 11, 1 June 2012, Pages 2524–2537, https://doi.org/10.1093/hmg/dds071
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Cleft palate, the most frequent congenital craniofacial birth defect, is a multifactorial condition induced by the interaction of genetic and environmental factors. In addition to complete cleft palate, a large number of human cases involve soft palate cleft and submucosal cleft palate. However, the etiology of these forms of cleft palate has not been well understood. T-box transcriptional factor (Tbx) family of transcriptional factors has distinct roles in a wide range of embryonic differentiation or response pathways. Here, we show that genetic disruption of Tbx1, a major candidate gene for the human congenital disorder 22q11.2 deletion syndrome (Velo-cardio-facial/DiGeorge syndrome), led to abnormal epithelial adhesion between the palate and mandible in mouse, resulting in various forms of cleft palate similar to human conditions. We found that hyperproliferative epithelium failed to undergo complete differentiation in _Tbx1_-null mice (_Tbx1_−/−). Inactivation of Tbx1 specifically in the keratinocyte lineage (Tbx1KCKO) resulted in an incomplete cleft palate confined to the anterior region of the palate. Interestingly, Tbx1 overexpression resulted in decreased cell growth and promoted cell-cycle arrest in MCF7 epithelial cells. These findings suggest that Tbx1 regulates the balance between proliferation and differentiation of keratinocytes and is essential for palatal fusion and oral mucosal differentiation. The impaired adhesion separation of the oral epithelium together with compromised palatal mesenchymal growth is an underlying cause for various forms of cleft palate phenotypes in _Tbx1_−/− mice. Our present study reveals new pathogenesis of incomplete and submucous cleft palate during mammalian palatogenesis.

© The Author 2012. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Topic:

• phenotype
• epithelium
• adhesions
• cleft palate
• embryo
• keratinocytes
• palate
• mice

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