title: Defective survival of proliferating Sertoli cells and androgen receptor function in a mouse model of the ATR-X syndrome.
abstract: X-linked ATR-X (alpha thalassemia, mental retardation, X-linked) syndrome in males is characterized by mental retardation, facial dysmorphism, alpha thalassemia and urogenital abnormalities, including small testes. It is unclear how mutations in the chromatin-remodeling protein ATRX cause these highly specific clinical features, since ATRX is widely expressed during organ development. To investigate the mechanisms underlying the testicular defects observed in ATR-X syndrome, we generated ScAtrxKO (Sertoli cell Atrx knockout) mice with Atrx specifically inactivated in the supporting cell lineage (Sertoli cells) of the mouse testis. ScAtrxKO mice developed small testes and discontinuous tubules, due to prolonged G2/M phase and apoptosis of proliferating Sertoli cells during fetal life. Apoptosis might be a consequence of the cell cycle defect. We also found that the onset of spermatogenesis was delayed in postnatal mice, with a range of spermatogenesis defects evident in adult ScAtrxKO mice. ATRX and the androgen receptor (AR) physically interact in the testis and in the Sertoli cell line TM4 and co-operatively activate the promoter of Rhox5, an important direct AR target. We also demonstrate that ATRX directly binds to the Rhox5 promoter in TM4 cells. Finally, gene expression of Rhox5 and of another AR-dependent gene, Spinlw1, was reduced in ScAtrxKO testes. These data suggest that ATRX can directly enhance the expression of androgen-dependent genes through physical interaction with AR. Recruitment of ATRX by DNA sequence-specific transcription factors could be a general mechanism by which ATRX achieves tissue-specific transcriptional regulation which could explain the highly specific clinical features of ATR-X syndrome when ATRX is mutated.
authors.affiliation: Molecular Genetics and Development Division, Prince Henry’s Institute of Medical Research, Clayton, VIC 3168, Australia.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bagheri-Fam
authors.forename: Anthony
authors.initials: A
authors.lastname: Argentaro
authors.forename: Terje
authors.initials: T
authors.lastname: Svingen
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Combes
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Sinclair
authors.forename: Peter
authors.initials: P
authors.lastname: Koopman
authors.forename: Vincent R
authors.initials: VR
authors.lastname: Harley
mesh_terms: D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D047468:Immunoprecipitation; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011944:Receptors, Androgen / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D012708:Sertoli Cells / Q000378:metabolism*; D013737:Testis / Q000002:abnormalities; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000075924:X-linked Nuclear Protein; D017085:alpha-Thalassemia / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D011944:Receptors, Androgen; C498048:Rhox5 protein, mouse; D014157:Transcription Factors; D004265:DNA Helicases; C490462:Atrx protein, mouse; D000075924:X-linked Nuclear Protein