Developmentally regulated SMAD2 and SMAD3 utilization directs activin signaling outcomes

• Published in: Developmental dynamics Vol. 238; no. 7; pp. 1688 - 1700
• Main Authors: Itman, Catherine, Small, Chris, Griswold, Michael, Nagaraja, Ankur K., Matzuk, Martin M., Brown, Chester W., Jans, David A., Loveland, Kate L.
• Format: Journal Article
• Language: English
• Published: New York Wiley‐Liss, Inc 01-07-2009
• Subjects: Activins - metabolism; Activins - pharmacology; Activins - physiology; Animals; Cell Differentiation - drug effects; Cell Differentiation - genetics; development; Dose-Response Relationship, Drug; Gene Expression Profiling; Gene Expression Regulation, Developmental - drug effects; Gene Expression Regulation, Developmental - physiology; Gja1; Male; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Transgenic; Models, Biological; morphogen gradient; Oligonucleotide Array Sequence Analysis; PDGF; Rarres1; Serpina5; Sertoli; Sertoli Cells - metabolism; Sertoli Cells - physiology; Signal Transduction - genetics; Smad2 Protein - genetics; Smad2 Protein - metabolism; Smad2 Protein - physiology; Smad3 Protein - genetics; Smad3 Protein - metabolism; Smad3 Protein - physiology; testis; TGFβ; TIG‐1
• ISSN: 1058-8388; 1097-0177
• DOI: 10.1002/dvdy.21995

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. Developmental Dynamics 238:1688–1700, 2009. © 2009 Wiley‐Liss, Inc.