Erk1/2 signaling is required for Tgf‐β2–induced suture closure

• Published in: Developmental dynamics 2006-05, Vol.235 (5), p.1292-1299
• Main Authors: Opperman, Lynne A., Fernandez, Claudia R., So, Sarah, Rawlins, Joseph T.
• Format: Article
• Language: English
• Subjects: cranial sutures; craniosynostosis; Erk1/2 signaling; intramembranous bone growth; mouse; TGF‐β2
• ISSN: 1058-8388; 1097-0177
• DOI: 10.1002/dvdy.20656

Transforming growth factors β (Tgf‐βs) act by means of Smad signaling pathways and may also interact with the mitogen‐activated protein kinase pathway. The hypothesis was tested that Erk1/2 signaling is required for Tgf‐β2–induced suture closure, by culturing embryonic mouse calvariae in the presence of Tgf‐β2 with or without Erk1/2 inhibitor PD98059 (PD). Suture widths were measured daily, and microdissected sutures and bones were homogenized and protein analyzed by Western blots. Tgf‐β2 induced narrowing of the sutures after 72 hr, an effect inhibited by treatment with PD. Erk1/2 and Egf but not Smad2/3 protein expression was up‐regulated by Tgf‐β2 calvarial tissues at 72 hr. PD inhibited endogenous and Tgf‐β2–stimulated Erk1/2 protein as well as Tgf‐β2–stimulated Egf, but increased Smad2/3 protein expression. In tissues harvested 0, 15, and 30 min after exposure to Tgf‐β2, Erk1/2 phosphorylation was up‐regulated after 15 min, an effect abrogated by the simultaneous addition of PD. In summary, Tgf‐β2 stimulated Erk1/2 phosphorylation and induced Egf and Erk1/2 expression, associated with suture closure after 72 hr. Blocking Erk1/2 activity with PD inhibited these effects but increased Smad2/3 expression. We postulate that Tgf‐β2 regulates suture closure directly by means of phosphorylation of Erk1/2 and indirectly by up‐regulating Erk1/2, a substrate for Fgf receptor signaling required for Fgf induction of premature suture obliteration. Developmental Dynamics 235:1292–1299, 2006. © 2005 Wiley‐Liss, Inc.