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

Stefan Bagheri-Fam, Anthony Argentaro, Terje Svingen, Alexander N. Combes, Andrew H. Sinclair, Peter Koopman, Vincent R. Harley

Research output: Contribution to journalJournal articleResearchpeer-review


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.
Original languageEnglish
JournalHuman Molecular Genetics
Issue number11
Pages (from-to)2213-2224
Number of pages12
Publication statusPublished - 2011
Externally publishedYes


  • Animals
  • Apoptosis
  • Cell Cycle
  • Cell Proliferation
  • Cells, Cultured
  • Chromatin Assembly and Disassembly
  • DNA Helicases
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation
  • Homeodomain Proteins
  • Immunoprecipitation
  • Male
  • Mental Retardation, X-Linked
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Nuclear Proteins
  • Promoter Regions, Genetic
  • Receptors, Androgen
  • Sequence Analysis, DNA
  • Sertoli Cells
  • Testis
  • Transcription Factors
  • alpha-Thalassemia
  • Rhox5 protein, mouse
  • EC 3.6.4.- DNA Helicases
  • EC Atrx protein, mouse
  • androgen receptor
  • follitropin
  • testosterone
  • alpha thalassemia, mental retardation, x linked syndrome
  • animal experiment
  • animal tissue
  • apoptosis
  • article
  • atrx gene
  • cell cycle G2 phase
  • cell cycle M phase
  • cell proliferation
  • cell survival
  • controlled study
  • developmental disorder
  • female
  • gene expression
  • gene inactivation
  • genetic transcription
  • male
  • mouse
  • nonhuman
  • priority journal
  • promoter region
  • protein interaction
  • regulator gene
  • rhox5 gene
  • Sertoli cell
  • spermatogenesis
  • testis development
  • testis function
  • Mus
  • Rodentia Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Mammals, Nonhuman Vertebrates, Nonhuman Mammals, Rodents, Vertebrates) - Muridae [86375] TM4 cell line cell_line mouse Sertoli cells mouse common mature, immature female, male strain-C57BL/6
  • mouse Rhox5 gene [Muridae] promoter, expression
  • mouse ScAtrxKO gene [Muridae] mouse sertoli cell Atrx gene
  • mouse Spinlw1 gene [Muridae] expression
  • DNA sequence-specific transcription factor
  • 02506, Cytology - Animal
  • 03502, Genetics - General
  • 03506, Genetics - Animal
  • 07002, Behavioral biology - General and comparative behavior
  • 07003, Behavioral biology - Animal behavior
  • 10064, Biochemistry studies - Proteins, peptides and amino acids
  • 15002, Blood - Blood and lymph studies
  • 15004, Blood - Blood cell studies
  • 15006, Blood - Blood, lymphatic and reticuloendothelial pathologies
  • 16504, Reproductive system - Physiology and biochemistry
  • 16506, Reproductive system - Pathology
  • 17006, Endocrine - Gonads and placenta
  • 25502, Development and Embryology - General and descriptive
  • 25503, Development and Embryology - Pathology
  • Behavior
  • Blood and Lymphatics
  • Development
  • Genetics
  • Molecular Genetics
  • Reproductive System
  • testicular disease reproductive system disease/male, endocrine disease/gonads
  • X-linked alpha-thalassemia-mental retardation-X-linked syndrome ATR-X syndrome congenital disease, genetic disease, behavioral and mental disorders, blood and lymphatic disease, reproductive system disease/male genetics
  • cell apoptosis
  • cell defective survival
  • cycle defect
  • nutritional support
  • organ development
  • organ function
  • receptor function
  • structural support
  • Biochemistry and Molecular Biophysics
  • Reproduction
  • Transport and Circulation
  • germ cell reproductive system
  • Sertoli cell reproductive system
  • testis reproductive system


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