Defective survival of proliferating Sertoli cells and androgen receptor function in a mouse model of the ATR-X syndrome

Bagheri-Fam, S, Argentaro, A, Svingen, T, Combes, AN, Sinclair, AH, Koopman, P and Harley, VR (2011) Defective survival of proliferating Sertoli cells and androgen receptor function in a mouse model of the ATR-X syndrome. Human Molecular Genetics, 20 11: 2213-2224. doi:10.1093/hmg/ddr109


Author Bagheri-Fam, S
Argentaro, A
Svingen, T
Combes, AN
Sinclair, AH
Koopman, P
Harley, VR
Title Defective survival of proliferating Sertoli cells and androgen receptor function in a mouse model of the ATR-X syndrome
Formatted title
Defective survival of proliferating Sertoli cells and androgen receptor function in a mouse model of the ATR-X syndrome
Journal name Human Molecular Genetics   Check publisher's open access policy
ISSN 0964-6906
1460-2083
Publication date 2011-06-01
Year available 2011
Sub-type Article (original research)
DOI 10.1093/hmg/ddr109
Open Access Status Not yet assessed
Volume 20
Issue 11
Start page 2213
End page 2224
Total pages 12
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Language eng
Subject 1311 Genetics
2716 Genetics (clinical)
1312 Molecular Biology
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.
Formatted 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.
©The Author 2011. Published by Oxford University Press. All rights reserved

Keyword Alpha-Thalassemia
Homeobox Gene
Protein Atrx
Sex Reversal
Chromosome Condensation
Dependent Manner
Tandem Repeats
Chromatin
Testis
Expression
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 334314
Institutional Status UQ
Additional Notes Erratum publication details:HMG Advance Access published July 6, 2011

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
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