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Defective survival of proliferating Sertoli cells and androgen receptor function in a mouse model of the ATR-X syndrome
- Source :
- Human molecular genetics. 20(11)
- Publication Year :
- 2011
-
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.
- Subjects :
- Male
X-linked Nuclear Protein
Apoptosis
Testicle
Biology
medicine.disease_cause
Mice
alpha-Thalassemia
Testis
Genetics
medicine
Animals
Immunoprecipitation
Promoter Regions, Genetic
Molecular Biology
Transcription factor
Genetics (clinical)
ATRX
Cells, Cultured
Cell Proliferation
Regulation of gene expression
Homeodomain Proteins
Mice, Knockout
Mutation
Sertoli Cells
Cell Cycle
DNA Helicases
Nuclear Proteins
General Medicine
Sequence Analysis, DNA
Cell cycle
Sertoli cell
Chromatin Assembly and Disassembly
Androgen receptor
Mice, Inbred C57BL
Disease Models, Animal
medicine.anatomical_structure
Gene Expression Regulation
Receptors, Androgen
Cancer research
Mental Retardation, X-Linked
Female
Transcription Factors
Subjects
Details
- ISSN :
- 14602083
- Volume :
- 20
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Human molecular genetics
- Accession number :
- edsair.doi.dedup.....c44bd43c34e5f6fbaab70139990e9812