TGF-beta signaling is essential for joint morphogenesis.
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.
Spagnoli
Anna
A
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. anna.spagnoli@vanderbilt.edu
O'Rear
Lynda
L
Chandler
Ronald L
RL
Granero-Molto
Froilan
F
Mortlock
Douglas P
DP
Gorska
Agnieszka E
AE
Weis
Jared A
JA
Longobardi
Lara
L
Chytil
Anna
A
Shimer
Kimberly
K
Moses
Harold L
HL
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*
D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II