Loss of ATRX in Chondrocytes Has Minimal Effects on Skeletal Development

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2009 Sep 24

PMID 19774083

Citations 15

Authors

Lauren A Solomon

Jennifer R Li

Nathalie G Berube

Frank Beier

Affiliations

Soon will be listed here.

Abstract

Background: Mutations in the human ATRX gene cause developmental defects, including skeletal deformities and dwarfism. ATRX encodes a chromatin remodeling protein, however the role of ATRX in skeletal development is currently unknown.

Methodology/principal Findings: We induced Atrx deletion in mouse cartilage using the Cre-loxP system, with Cre expression driven by the collagen II (Col2a1) promoter. Growth rate, body size and weight, and long bone length did not differ in Atrx(Col2cre) mice compared to control littermates. Histological analyses of the growth plate did not reveal any differences between control and mutant mice. Expression patterns of Sox9, a transcription factor required for cartilage morphogenesis, and p57, a marker of cell cycle arrest and hypertrophic chondrocyte differentiation, was unaffected. However, loss of ATRX in cartilage led to a delay in the ossification of the hips in some mice. We also observed hindlimb polydactily in one out of 61 mutants.

Conclusions/significance: These findings indicate that ATRX is not directly required for development or growth of cartilage in the mouse, suggesting that the short stature in ATR-X patients is caused by defects in cartilage-extrinsic mechanisms.

Citing Articles

ATRX silences Cartpt expression in osteoblastic cells during skeletal development.

Chen Y, Jiang M, Leynes C, Adeyeye M, Majano C, Ibrahim B J Clin Invest. 2025; 135(1).

PMID: 39744954 PMC: 11684799. DOI: 10.1172/JCI163587.

A new mouse model of ATR-X syndrome carrying a common patient mutation exhibits neurological and morphological defects.

Tillotson R, Yan K, Ruston J, DeYoung T, Cordova A, Turcotte-Cardin V Hum Mol Genet. 2023; 32(15):2485-2501.

PMID: 37171606 PMC: 10360390. DOI: 10.1093/hmg/ddad075.

Loss of Nexmif results in the expression of phenotypic variability and loss of genomic integrity.

Stekelenburg C, Blouin J, Santoni F, Zaghloul N, OHare E, Dusaulcy R Sci Rep. 2022; 12(1):13815.

PMID: 35970867 PMC: 9378738. DOI: 10.1038/s41598-022-17845-1.

Neurodevelopmental Disorders Caused by Defective Chromatin Remodeling: Phenotypic Complexity Is Highlighted by a Review of ATRX Function.

Timpano S, Picketts D Front Genet. 2020; 11:885.

PMID: 32849845 PMC: 7432156. DOI: 10.3389/fgene.2020.00885.

Exposure to the RXR Agonist SR11237 in Early Life Causes Disturbed Skeletal Morphogenesis in a Rat Model.

Dupuis H, Pest M, Hadzic E, Vo T, Hardy D, Beier F Int J Mol Sci. 2019; 20(20).

PMID: 31635173 PMC: 6829207. DOI: 10.3390/ijms20205198.

References

Hoffman L, Weston A, Underhill T . Molecular mechanisms regulating chondroblast differentiation. J Bone Joint Surg Am. 2003; 85-A Suppl 2:124-32. DOI: 10.2106/00004623-200300002-00017. View

Wang G, Woods A, Agoston H, Ulici V, Glogauer M, Beier F . Genetic ablation of Rac1 in cartilage results in chondrodysplasia. Dev Biol. 2007; 306(2):612-23. DOI: 10.1016/j.ydbio.2007.03.520. View

Ritchie K, Seah C, Moulin J, Isaac C, Dick F, Berube N . Loss of ATRX leads to chromosome cohesion and congression defects. J Cell Biol. 2008; 180(2):315-24. PMC: 2213576. DOI: 10.1083/jcb.200706083. View

Picketts D, Higgs D, Bachoo S, Blake D, Quarrell O, Gibbons R . ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR-X syndrome. Hum Mol Genet. 1996; 5(12):1899-907. DOI: 10.1093/hmg/5.12.1899. View

Kronenberg H . Developmental regulation of the growth plate. Nature. 2003; 423(6937):332-6. DOI: 10.1038/nature01657. View

Ballock R, OKeefe R . Physiology and pathophysiology of the growth plate. Birth Defects Res C Embryo Today. 2003; 69(2):123-43. DOI: 10.1002/bdrc.10014. View

Berube N, Mangelsdorf M, Jagla M, Vanderluit J, Garrick D, Gibbons R . The chromatin-remodeling protein ATRX is critical for neuronal survival during corticogenesis. J Clin Invest. 2005; 115(2):258-67. PMC: 544602. DOI: 10.1172/JCI22329. View

Terpstra L, Prudhomme J, Arabian A, Takeda S, Karsenty G, Dedhar S . Reduced chondrocyte proliferation and chondrodysplasia in mice lacking the integrin-linked kinase in chondrocytes. J Cell Biol. 2003; 162(1):139-48. PMC: 2172728. DOI: 10.1083/jcb.200302066. View

Gibbons R, Wada T, Fisher C, Malik N, Mitson M, Steensma D . Mutations in the chromatin-associated protein ATRX. Hum Mutat. 2008; 29(6):796-802. DOI: 10.1002/humu.20734. View

10.

Maestroni G . Neurohormones and catecholamines as functional components of the bone marrow microenvironment. Ann N Y Acad Sci. 2001; 917:29-37. DOI: 10.1111/j.1749-6632.2000.tb05370.x. View

11.

Seah C, Levy M, Jiang Y, Mokhtarzada S, Higgs D, Gibbons R . Neuronal death resulting from targeted disruption of the Snf2 protein ATRX is mediated by p53. J Neurosci. 2008; 28(47):12570-80. PMC: 6671724. DOI: 10.1523/JNEUROSCI.4048-08.2008. View

12.

Gibbons R, Picketts D, Villard L, Higgs D . Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome). Cell. 1995; 80(6):837-45. DOI: 10.1016/0092-8674(95)90287-2. View

13.

Gibbons R, Brueton L, Buckle V, Burn J, Clayton-Smith J, Davison B . Clinical and hematologic aspects of the X-linked alpha-thalassemia/mental retardation syndrome (ATR-X). Am J Med Genet. 1995; 55(3):288-99. DOI: 10.1002/ajmg.1320550309. View

14.

Eisen J, Sweder K, HANAWALT P . Evolution of the SNF2 family of proteins: subfamilies with distinct sequences and functions. Nucleic Acids Res. 1995; 23(14):2715-23. PMC: 307096. DOI: 10.1093/nar/23.14.2715. View

15.

Takeda S . Central control of bone remodeling. Biochem Biophys Res Commun. 2005; 328(3):697-9. DOI: 10.1016/j.bbrc.2004.11.071. View

16.

Gibbons R . Alpha thalassaemia-mental retardation, X linked. Orphanet J Rare Dis. 2006; 1:15. PMC: 1464382. DOI: 10.1186/1750-1172-1-15. View

17.

Zelzer E, Olsen B . The genetic basis for skeletal diseases. Nature. 2003; 423(6937):343-8. DOI: 10.1038/nature01659. View

18.

Akiyama H, Chaboissier M, Martin J, Schedl A, de Crombrugghe B . The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev. 2002; 16(21):2813-28. PMC: 187468. DOI: 10.1101/gad.1017802. View

19.

DeLise A, Fischer L, Tuan R . Cellular interactions and signaling in cartilage development. Osteoarthritis Cartilage. 2000; 8(5):309-34. DOI: 10.1053/joca.1999.0306. View

20.

Ducy P, Schinke T, Karsenty G . The osteoblast: a sophisticated fibroblast under central surveillance. Science. 2000; 289(5484):1501-4. DOI: 10.1126/science.289.5484.1501. View