title: TGF-beta signaling is essential for joint morphogenesis.
abstract: Despite its clinical significance, joint morphogenesis is still an obscure process. In this study, we determine the role of transforming growth factor beta (TGF-beta) signaling in mice lacking the TGF-beta type II receptor gene (Tgfbr2) in their limbs (Tgfbr2(PRX-1KO)). In Tgfbr2(PRX-1KO) mice, the loss of TGF-beta responsiveness resulted in the absence of interphalangeal joints. The Tgfbr2(Prx1KO) joint phenotype is similar to that in patients with symphalangism (SYM1-OMIM185800). By generating a Tgfbr2-green fluorescent protein-beta-GEO-bacterial artificial chromosome beta-galactosidase reporter transgenic mouse and by in situ hybridization and immunofluorescence, we determined that Tgfbr2 is highly and specifically expressed in developing joints. We demonstrated that in Tgfbr2(PRX-1KO) mice, the failure of joint interzone development resulted from an aberrant persistence of differentiated chondrocytes and failure of Jagged-1 expression. We found that TGF-beta receptor II signaling regulates Noggin, Wnt9a, and growth and differentiation factor-5 joint morphogenic gene expressions. In Tgfbr2(PRX-1KO) growth plates adjacent to interphalangeal joints, Indian hedgehog expression is increased, whereas Collagen 10 expression decreased. We propose a model for joint development in which TGF-beta signaling represents a means of entry to initiate the process.
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. anna.spagnoli@vanderbilt.edu
authors.forename: Anna
authors.initials: A
authors.lastname: Spagnoli
authors.forename: Lynda
authors.initials: L
authors.lastname: O'Rear
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Chandler
authors.forename: Froilan
authors.initials: F
authors.lastname: Granero-Molto
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Mortlock
authors.forename: Agnieszka E
authors.initials: AE
authors.lastname: Gorska
authors.forename: Jared A
authors.initials: JA
authors.lastname: Weis
authors.forename: Lara
authors.initials: L
authors.lastname: Longobardi
authors.forename: Anna
authors.initials: A
authors.lastname: Chytil
authors.forename: Kimberly
authors.initials: K
authors.lastname: Shimer
authors.forename: Harold L
authors.initials: HL
authors.lastname: Moses
mesh_terms: D000818:Animals; D004622:Embryo, Mammalian; D005121:Extremities; D007596:Joints / Q000737:chemistry / Q000196:embryology / Q000254:growth & development*; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis / Q000172:deficiency; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II