ATXN1 Protein Family and CIC Regulate Extracellular Matrix Remodeling and Lung Alveolarization

Yoontae Lee, John D. Fryer, Hyojin Kang, Juan Crespo-Barreto, Aaron B. Bowman, Yan Gao, Juliette J. Kahle, Jeong Soo Hong, Farrah Kheradmand, Harry T. Orr, Milton J. Finegold, Huda Y. Zoghbi

Research output: Contribution to journalArticlepeer-review

64 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)746-757
Number of pages12
JournalDevelopmental Cell
Issue number4
StatePublished - Oct 18 2011

Bibliographical note

Funding Information:
We thank Dr. Moghaddam for helping us with inflated fixation of lung tissues and Jounghwa Won for the morphometric analysis. We are grateful to members of the Zoghbi laboratory for helpful discussions and comments on the manuscript. The morphological studies were performed in the Molecular Morphology Core Laboratory of the NIDDK-sponsored Texas Medical Center Digestive Disease Center, DK 56338. This research was supported by NIH grants NS27699 and HD24064 to H.Y.Z. H.Y.Z. is an investigator with the Howard Hughes Medical Institute.

Fingerprint Dive into the research topics of 'ATXN1 Protein Family and CIC Regulate Extracellular Matrix Remodeling and Lung Alveolarization'. Together they form a unique fingerprint.

Cite this