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Human Molecular Genetics Advance Access published online on November 2, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl427
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© 2006 Oxford University Press

Intragenic Deletion of Tgif Causes Defects in Brain Development

Chenzhong Kuang1, Yan Xiao1, Ling Yang2, Qian Chen1, Zhenzhen Wang2, Simon J. Conway3 and Yan Chen1,2,*

1 Department of Medical and Molecular Genetics, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, 46202, USA 2 Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai 200031, China 3 Cardiovascular Development Group, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, 46202, USA

* ychen3{at}iupui.edu

Received September 11, 2006; Revised October 26, 2006; Accepted October 26, 2006

TG-interacting factor (TGIF) is a homeodomain-containing protein and functions as a transcriptional repressor within the TGF-ß and retinoic acid signaling pathways. Heterozygous mutations of TGIF have been found in patients with holoprosencephaly, which is the most common congenital brain malformation in humans. However, targeted null deletions of the entire Tgif gene in mice surprisingly revealed no apparent brain defects. We report here that deletion of the third exon of Tgif gene resulted in a defined spectrum of brain developmental defects including exencephaly, microcephaly, holoprosencephaly, and abnormalities in embryonic brain ventricle formation and cleavage. These defects could be detected in mice both heterozygous and homozygous for the targeted Tgif deletion. Moreover, expression of dorsal-ventral patterning genes including Shh, Pax6 and Nkx2.2 was altered. The ventricular neuroepithelium exhibited focalized increase of cell proliferation rate and resultant tissue expansion. The incidence of brain abnormalities within the mutant mice was dependent on its genetic background, suggesting that additional genetic modifiers functionally interact with Tgif during embryonic brain development. The Tgif deficient mouse, therefore, would serve as a useful model that can be used to unravel the genetic complexity implicated in the pathogenesis of holoprosencephaly.


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P. A. Gongal and A. J. Waskiewicz
Zebrafish model of holoprosencephaly demonstrates a key role for TGIF in regulating retinoic acid metabolism
Hum. Mol. Genet., February 14, 2008; 17(4): 525 - 538.
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