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

doi:10.1016/j.devcel.2011.08.017

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

Neuroscience

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

66 Scopus citations

Abstract

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 language	English (US)
Pages (from-to)	746-757
Number of pages	12
Journal	Developmental Cell
Volume	21
Issue number	4
DOIs	https://doi.org/10.1016/j.devcel.2011.08.017
State	Published - Oct 18 2011

ASJC Scopus subject areas

Molecular Biology
Biochemistry, Genetics and Molecular Biology(all)
Developmental Biology
Cell Biology

Access to Document

10.1016/j.devcel.2011.08.017

Cite this

@article{2a4f50aa2daa4d3d9976e729f623f731,

title = "ATXN1 Protein Family and CIC Regulate Extracellular Matrix Remodeling and Lung Alveolarization",

abstract = "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.",

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

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. ",

year = "2011",

month = oct,

day = "18",

doi = "10.1016/j.devcel.2011.08.017",

language = "English (US)",

volume = "21",

pages = "746--757",

journal = "Developmental Cell",

issn = "1534-5807",

publisher = "Cell Press",

number = "4",

}

TY - JOUR

T1 - ATXN1 Protein Family and CIC Regulate Extracellular Matrix Remodeling and Lung Alveolarization

AU - Lee, Yoontae

AU - Fryer, John D.

AU - Kang, Hyojin

AU - Crespo-Barreto, Juan

AU - Bowman, Aaron B.

AU - Gao, Yan

AU - Kahle, Juliette J.

AU - Hong, Jeong Soo

AU - Kheradmand, Farrah

AU - Orr, Harry T.

AU - Finegold, Milton J.

AU - Zoghbi, Huda Y.

N1 - 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.

PY - 2011/10/18

Y1 - 2011/10/18

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=80054734186&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80054734186&partnerID=8YFLogxK

U2 - 10.1016/j.devcel.2011.08.017

DO - 10.1016/j.devcel.2011.08.017

M3 - Article

C2 - 22014525

AN - SCOPUS:80054734186

SN - 1534-5807

VL - 21

SP - 746

EP - 757

JO - Developmental Cell

JF - Developmental Cell

IS - 4

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this