이윤태 (Baylor College of Medicine, 현 POSTECH) | 한빛사논문 > 한빛사

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Baylor College of Medicine, 현 POSTECH

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Dev. Cell, 21, 746–757, October 18, 2011 | DOI 10.1016/j.devcel.2011.08.017 ATXN1 Protein Family and CIC Regulate Extracellular Matrix Remodeling and Lung Alveolarization

Abstract

Yoontae Lee,^1,6,7,9 John D. Fryer,^1,6 Hyojin Kang,^1,6 Juan Crespo-Barreto,⁵ Aaron B. Bowman,^1,10 Yan Gao,^1,6 Juliette J. Kahle,^1,6 Jeong Soo Hong,³ Farrah Kheradmand,³ Harry T. Orr,⁸ Milton J. Finegold,⁴ and Huda Y. Zoghbi^1,2,5,6,7,*

¹Department of Molecular and Human Genetics
²Department of Neuroscience
³Department of Medicine
⁴Department of Pathology
⁵Interdepartmental Program in Cell and Molecular Biology
⁶Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital
⁷Howard Hughes Medical Institute Baylor College of Medicine, Houston, TX 77030, USA
⁸Institute of Human Genetics, Department of Biochemistry, Biophysics and Molecular Biology, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
⁹Present address: Department of Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, Republic of Korea
¹⁰Present address: Department of Neurology and Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University Medical Center, Nashville, TN 37232, USA

*Correspondence: Huda Y. Zoghbi

SUMMARY
Although expansion of CAG repeats in ATAXIN1 (ATXN1) causes Spinocerebellar ataxia type 1, the functions of ATXN1 and ATAXIN1-Like (ATXN1L) remain poorly understood. To investigate the function of these proteins, we generated and characterized Atxn1L^-/- and Atxn1^-/-; Atxn1L^-/- mice. Atxn1L^-/- mice have hydrocephalus, omphalocele, and lung alveolarization defects. These phenotypes are more penetrant and severe in Atxn1^-/-; Atxn1L^-/- mice, suggesting that ATXN1 and ATXN1L are functionally redundant. Upon pursuing the molecular mechanism, we discovered that several Matrix metalloproteinase (Mmp) genes are overexpressed and that the transcriptional repressor Capicua (CIC) is destabilized in Atxn1L^-/- lungs. Consistent with this, Cic deficiency causes lung alveolarization defect. Loss of either ATXN1L or CIC derepresses Etv4, an activator for Mmp genes, thereby mediating MMP9 overexpression. These findings demonstrate a critical role of ATXN1/ATXN1L-CIC complexes in extracellular matrix (ECM) remodeling during development and their potential roles in pathogenesis of disorders affecting ECM remodeling.

논문정보

형식Research article
게재일2011년 10월 (BRIC 등록일 )
연구진국외 연구진
분야 생명과학 > 세포생물학

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