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Article: Receptor tyrosine kinase-like orphan receptor 2 (ROR2) and Indian hedgehog regulate digit outgrowth mediated by the phalanx-forming region

TitleReceptor tyrosine kinase-like orphan receptor 2 (ROR2) and Indian hedgehog regulate digit outgrowth mediated by the phalanx-forming region
Authors
Issue Date2010
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings Of The National Academy Of Sciences Of The United States Of America, 2010, v. 107 n. 32, p. 14211-14216 How to Cite?
AbstractElongation 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 themouse,whichis diminishedinBDB1 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 inmammals. Genetic interaction experiments as well as pathway analysis in BDB1 mice suggest that Indian hedgehog and WNT/β-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.
Persistent Identifierhttp://hdl.handle.net/10722/129094
ISSN
2015 Impact Factor: 9.423
2015 SCImago Journal Rankings: 6.883
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Deutsche ForschungsgemeinschaftSFB 577
Research Grants Council of Hong KongHKU760608M
Funding Information:

We thank Kathrin Seidel and Norbert Brieske for their expert technical assistance and the animal facility of the Max Planck Institute for Molecular Genetics, especially Janine Wetzel, for mouse work assistance. 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.).

References

 

DC FieldValueLanguage
dc.contributor.authorWitte, Fen_HK
dc.contributor.authorChan, Den_HK
dc.contributor.authorEconomides, ANen_HK
dc.contributor.authorMundlos, Sen_HK
dc.contributor.authorStricker, Sen_HK
dc.date.accessioned2010-12-23T08:32:26Z-
dc.date.available2010-12-23T08:32:26Z-
dc.date.issued2010en_HK
dc.identifier.citationProceedings Of The National Academy Of Sciences Of The United States Of America, 2010, v. 107 n. 32, p. 14211-14216en_HK
dc.identifier.issn0027-8424en_HK
dc.identifier.urihttp://hdl.handle.net/10722/129094-
dc.description.abstractElongation 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 themouse,whichis diminishedinBDB1 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 inmammals. Genetic interaction experiments as well as pathway analysis in BDB1 mice suggest that Indian hedgehog and WNT/β-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.en_HK
dc.languageengen_US
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.orgen_HK
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of Americaen_HK
dc.subject.meshAnimalsen_HK
dc.subject.meshBone Morphogenetic Proteinsen_HK
dc.subject.meshExtremities - growth & developmenten_HK
dc.subject.meshHedgehog Proteins - genetics - physiologyen_HK
dc.subject.meshMiceen_HK
dc.subject.meshMice, Mutant Strainsen_HK
dc.subject.meshMutation, Missenseen_HK
dc.subject.meshReceptor Tyrosine Kinase-like Orphan Receptors - genetics - physiologyen_HK
dc.subject.meshSignal Transductionen_HK
dc.subject.meshToe Phalanges - growth & development - physiologyen_HK
dc.subject.meshWnt Proteinsen_HK
dc.titleReceptor tyrosine kinase-like orphan receptor 2 (ROR2) and Indian hedgehog regulate digit outgrowth mediated by the phalanx-forming regionen_HK
dc.typeArticleen_HK
dc.identifier.emailChan, D:chand@hkucc.hku.hken_HK
dc.identifier.authorityChan, D=rp00540en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1073/pnas.1009314107en_HK
dc.identifier.pmid20660756-
dc.identifier.pmcidPMC2922544-
dc.identifier.scopuseid_2-s2.0-77956283416en_HK
dc.identifier.hkuros177861en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77956283416&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume107en_HK
dc.identifier.issue32en_HK
dc.identifier.spage14211en_HK
dc.identifier.epage14216en_HK
dc.identifier.isiWOS:000280767700044-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridWitte, F=24436519800en_HK
dc.identifier.scopusauthoridChan, D=7402216545en_HK
dc.identifier.scopusauthoridEconomides, AN=35263794500en_HK
dc.identifier.scopusauthoridMundlos, S=7005248176en_HK
dc.identifier.scopusauthoridStricker, S=7005436014en_HK

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