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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.

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