title: Sertoli cell-specific expression of metastasis-associated protein 2 (MTA2) is required for transcriptional regulation of the follicle-stimulating hormone receptor (FSHR) gene during spermatogenesis.
abstract: BACKGROUND
  Desensitization of FSH response by down-regulation of FSHR transcription is critical for FSH action.
  
  
  RESULTS
  Chromatin modifier MTA2 participates in the down-regulation of FSHR transcription.
  
  
  CONCLUSIONS
  The FSH/Ar/MTA2 cascade may serve as an indispensable negative feedback mechanism to modulate FSH transduction events in Sertoli cells.
  
  
  CONCLUSIONS
  Our findings provide new insights into mechanisms by which FSH is deregulated in male infertile patients. The effect of follicle-stimulating hormone (FSH) on spermatogenesis is modulated at a fundamental level by controlling the number of competent receptors present at the surface of Sertoli cells (SCs). One underlying mechanism is the down-regulation of the expression levels of the FSH receptor (FSHR) gene after exposure to FSH. Here we report that metastasis-associated protein 2 (MTA2), a component of histone deacetylase and nucleosome-remodeling complexes, as a gene product induced directly by testosterone or indirectly by FSH, is exclusively expressed in SCs. Stimulation of SCs with FSH is accompanied by up-regulation of MTA2 expression and enhancement of deacetylase activity. This effect requires the integrity of functional androgen receptor. Furthermore, MTA2 is a potent corepressor of FSHR transcription, because it can recruit histone deacetylase-1 onto the FSHR promoter and participates in the down-regulation of FSHR expression upon FSH treatment. Abolishment of endogenous MTA2 by siRNA treatment disrupted the desensitization of the FSH response and thereafter impaired the FSH-dependent secretory function of SCs. From a clinical standpoint, deregulated expression of MTA2 in SCs of human pathological testes negatively correlates to the deregulated level of serum FSH. Overall, our present results provide the first evidence that the FSH/androgen receptor/MTA2 cascade may serve as an indispensable negative feedback mechanism to modulate the transduction events of SCs in response to FSH. These data also underscore an unexpected reproductive facet of MTA2, which may operate as a novel integrator linking synergistic actions of FSH and androgen signaling in SCs.
authors.affiliation: Department of Human Anatomy, Histology, and Embryology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Shun
authors.initials: S
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Chuchao
authors.initials: C
authors.lastname: Zhu
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.forename: Jinshan
authors.initials: J
authors.lastname: Zhang
authors.forename: Jie
authors.initials: J
authors.lastname: Zhao
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
authors.forename: Teng
authors.initials: T
authors.lastname: Li
authors.forename: Yuanqiang
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000818:Animals; D005640:Follicle Stimulating Hormone / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D051381:Rats; D017207:Rats, Sprague-Dawley; D011962:Receptors, FSH / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D012708:Sertoli Cells / Q000378:metabolism*; D013091:Spermatogenesis; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
chemical_list: C529798:Mta2 protein, mouse; D011962:Receptors, FSH; D012097:Repressor Proteins; D015534:Trans-Activators; D005640:Follicle Stimulating Hormone; C120917:MTA2 protein, human; D006655:Histone Deacetylases