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Published online June 18, 2007
doi:10.1083/jcb.200611031
The Journal of Cell Biology, Vol. 177, No. 6, 1105-1117
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Spagnoli et al.
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Article

TGF-ß signaling is essential for joint morphogenesis



Anna Spagnoli1,3, Lynda O'Rear1, Ronald L. Chandler2, Froilan Granero-Molto1, Douglas P. Mortlock2, Agnieszka E. Gorska3, Jared A. Weis1, Lara Longobardi1, Anna Chytil3, Kimberly Shimer1, and Harold L. Moses3

1 Department of Pediatrics, 2 Department of Molecular Physiology and Biophysics, and 3 Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232

Correspondence to Anna Spagnoli: anna.spagnoli{at}vanderbilt.edu

Despite its clinical significance, joint morphogenesis is still an obscure process. In this study, we determine the role of transforming growth factor ß (TGF-ß) signaling in mice lacking the TGF-ß type II receptor gene (Tgfbr2) in their limbs (Tgfbr2PRX-1KO). In Tgfbr2PRX-1KO mice, the loss of TGF-ß 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–ß–GEO–bacterial artificial chromosome ß-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 Tgfbr2PRX-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-ß 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-ß signaling represents a means of entry to initiate the process.

Abbreviations used in this paper: BAC, bacterial artificial chromosome; BMP, bone morphogenic protein; DNIIR, dominant-negative Tgfbr2; GDF-5, growth and differentiation factor-5; Ihh, Indian hedgehog; LCM, laser capture microdissection; micro-CT; microcomputed tomography; PTH-rP, parathyroid hormone–related protein; TßR, TGF-ß receptor; WIB, Western immunoblotting.


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