TGF-β signaling is essential for joint morphogenesis

Anna Spagnoli, Lynda O'Rear, Ronald L. Chandler, Froilan Granero-Molto, Douglas P. Mortlock, Agnieszka E. Gorska, Jared A. Weis, Lara Longobardi, Anna Chytil, Kimberly Shimer, Harold L. Moses

Research output: Contribution to journalArticle

106 Citations (Scopus)

Abstract

Despite its clinical significance, joint morphogenesis is still an obscure process. In this study, we determine the role of transforming growth factor β (TGF-β) signaling in mice lacking the TGF-β type II receptor gene (Tgfbr2) in their limbs (Tgfbr2PRX-1KO). In Tgfbr2 PRX-1KO mice, the loss of TGF-β responsiveness resulted in the absence of interphalangeal joints. The Tgfbr2Prx1KO joint phenotype is similar to that in patients with symphalangism (SYM1-OMIM185800). By generating a Tgfbr2-green fluorescent protein-β-GEO-bacterial arti-ficial chromosome β-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-β receptor II signaling regulates Noggin, Wnt9a, and growth and differentiation factor-5 joint morphogenic gene expressions. In Tgfbr2PRX-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-β signaling represents a means of entry to initiate the process.

Original languageEnglish (US)
Pages (from-to)1105-1117
Number of pages13
JournalJournal of Cell Biology
Volume177
Issue number6
DOIs
StatePublished - Jun 18 2007

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Transforming Growth Factors
Morphogenesis
Joints
Growth Factor Receptors
Growth Differentiation Factor 5
Galactosidases
Growth Plate
Hedgehogs
Chondrocytes
Green Fluorescent Proteins
Transgenic Mice
In Situ Hybridization
Fluorescent Antibody Technique
Collagen
Extremities
Chromosomes
Phenotype
Gene Expression
Genes

ASJC Scopus subject areas

  • Cell Biology

Cite this

Spagnoli, A., O'Rear, L., Chandler, R. L., Granero-Molto, F., Mortlock, D. P., Gorska, A. E., ... Moses, H. L. (2007). TGF-β signaling is essential for joint morphogenesis. Journal of Cell Biology, 177(6), 1105-1117. https://doi.org/10.1083/jcb.200611031

TGF-β signaling is essential for joint morphogenesis. / Spagnoli, Anna; O'Rear, Lynda; Chandler, Ronald L.; Granero-Molto, Froilan; Mortlock, Douglas P.; Gorska, Agnieszka E.; Weis, Jared A.; Longobardi, Lara; Chytil, Anna; Shimer, Kimberly; Moses, Harold L.

In: Journal of Cell Biology, Vol. 177, No. 6, 18.06.2007, p. 1105-1117.

Research output: Contribution to journalArticle

Spagnoli, A, O'Rear, L, Chandler, RL, Granero-Molto, F, Mortlock, DP, Gorska, AE, Weis, JA, Longobardi, L, Chytil, A, Shimer, K & Moses, HL 2007, 'TGF-β signaling is essential for joint morphogenesis', Journal of Cell Biology, vol. 177, no. 6, pp. 1105-1117. https://doi.org/10.1083/jcb.200611031
Spagnoli A, O'Rear L, Chandler RL, Granero-Molto F, Mortlock DP, Gorska AE et al. TGF-β signaling is essential for joint morphogenesis. Journal of Cell Biology. 2007 Jun 18;177(6):1105-1117. https://doi.org/10.1083/jcb.200611031
Spagnoli, Anna ; O'Rear, Lynda ; Chandler, Ronald L. ; Granero-Molto, Froilan ; Mortlock, Douglas P. ; Gorska, Agnieszka E. ; Weis, Jared A. ; Longobardi, Lara ; Chytil, Anna ; Shimer, Kimberly ; Moses, Harold L. / TGF-β signaling is essential for joint morphogenesis. In: Journal of Cell Biology. 2007 ; Vol. 177, No. 6. pp. 1105-1117.
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