title: Developmentally regulated SMAD2 and SMAD3 utilization directs activin signaling outcomes.
abstract: Activin is required for testis development. Activin signals via phosphorylation and nuclear accumulation of SMAD2 and SMAD3. We present novel findings of developmentally regulated activin signaling leading to specific transcriptional outcomes in testicular Sertoli cells. In immature, proliferating, Sertoli cells, activin A induces nuclear accumulation of SMAD3, but not SMAD2, although both proteins become phosphorylated. In postmitotic differentiating cells, both SMAD proteins accumulate in the nucleus. Furthermore, immature Sertoli cells are sensitive to activin dosage; higher concentrations induce maximal SMAD3 nuclear accumulation and a small increase in nuclear SMAD2. Microarray analysis identified distinct transcriptional outcomes correlating with differential SMAD utilization and new activin target genes, including Gja1 and Serpina5, which are essential for Sertoli cell development and male fertility. In transgenic mice with altered activin bioactivity that display fertility phenotypes, Gja1 and Serpina5 are significantly altered. Thus, differential SMAD utilization in response to activin features during Sertoli cell maturation.
authors.affiliation: Department of Biochemistry &Molecular Biology, Monash University, Melbourne, Australia.
authors.forename: Catherine
authors.initials: C
authors.lastname: Itman
authors.forename: Chris
authors.initials: C
authors.lastname: Small
authors.forename: Michael
authors.initials: M
authors.lastname: Griswold
authors.forename: Ankur K
authors.initials: AK
authors.lastname: Nagaraja
authors.forename: Martin M
authors.initials: MM
authors.lastname: Matzuk
authors.forename: Chester W
authors.initials: CW
authors.lastname: Brown
authors.forename: David A
authors.initials: DA
authors.lastname: Jans
authors.forename: Kate L
authors.initials: KL
authors.lastname: Loveland
mesh_terms: D028341:Activins / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D012708:Sertoli Cells / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D028341:Activins