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          Institute: MPI für molekulare Genetik     Collection: Research Group Development and Disease     Display Documents



  history
ID: 539727.0, MPI für molekulare Genetik / Research Group Development and Disease
Receptor tyrosine kinase-like orphan receptor 2 (ROR2) and Indian hedgehog regulate digit outgrowth mediated by the phalanx-forming region
Authors:Witte, F.; Chan, D.; Economides, A. N.; Mundlos, S.; Stricker, S.
Language:English
Research Context:This project was funded by Deutsche Forschungsgemeinschaft Grant SFB 577 (to S.S. and S.M.) and Research Grants Council of Hong Kong Grant HKU760608M (to D.C.).
Date of Publication (YYYY-MM-DD):2010-08-10
Title of Journal:Proceedings of the National Academy of Sciences U S A
Journal Abbrev.:Proc Natl Acad Sci U S A
Volume:107
Issue / Number:32
Start Page:14211
End Page:14216
Copyright:©2010 by the National Academy of Sciences
Review Status:not specified
Audience:Experts Only
Abstract / Description:Elongation of the digit rays resulting in the formation of a defined number of phalanges is a process poorly understood in mammals, whereas in the chicken distal mesenchymal bone morphogenetic protein (BMP) signaling in the so-called phalanx-forming region (PFR) or digit crescent (DC) seems to be involved. The human brachydactylies (BDs) are inheritable conditions characterized by variable degrees of digit shortening, thus providing an ideal model to analyze the development and elongation of phalanges. We used a mouse model for BDB1 (Ror2(W749X/W749X)) lacking middle phalanges and show that a signaling center corresponding to the chick PFR exists in the mouse, which is diminished in BDB1 mice. This resulted in a strongly impaired elongation of the digit condensations due to reduced chondrogenic commitment of undifferentiated distal mesenchymal cells. We further show that a similar BMP-based mechanism accounts for digit shortening in a mouse model for the closely related condition BDA1 (Ihh(E95K/E95K)), altogether indicating the functional significance of the PFR in mammals. Genetic interaction experiments as well as pathway analysis in BDB1 mice suggest that Indian hedgehog and WNT/beta-catenin signaling, which we show is inhibited by receptor tyrosine kinase-like orphan receptor 2 (ROR2) in distal limb mesenchyme, are acting upstream of BMP signaling in the PFR.
Free Keywords:bone morphogenetic protein signaling;
brachydactyly;
cartilage;
limb development;
Wnt signaling
Comment of the Author/Creator:To whom correspondence should be addressed.
E-mail: strick_s@molgen.mpg.de.
External Publication Status:published
Document Type:Article
Communicated by:Stefan Mundlos
Affiliations:MPI für molekulare Genetik
External Affiliations:1.Institute for Medical Genetics, Charité, University Medicine Berlin, 13353 Berlin, Germany;
2.Institut für Chemie/Biochemie, Freie Universität Berlin, 14195 Berlin, Germany;
3.Department of Biochemistry, The University of Hong Kong, Pokfulam, Hong Kong, China;
4.Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA;
5.Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, 13353 Berlin, Germany.
Identifiers:ISSN:0027-8424 [ID No:1]
URL:http://www.ncbi.nlm.nih.gov/pubmed/20660756 [ID No:2]
DOI:10.1073/pnas.1009314107 [ID No:3]
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