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Article: Missense mutations in IHH impair Indian hedgehog signaling in C3H10T1/2 cells: Implications for brachydactyly type A1, and new targets for hedgehog signaling

TitleMissense mutations in IHH impair Indian hedgehog signaling in C3H10T1/2 cells: Implications for brachydactyly type A1, and new targets for hedgehog signaling
Authors
Issue Date2010
PublisherVersita. The Journal's web site is located at http://www.cmbl.org.pl
Citation
Cellular And Molecular Biology Letters, 2010, v. 15 n. 1, p. 153-176 How to Cite?
AbstractHeterozygous missense mutations in IHH result in Brachydactyly type A1 (BDA1; OMIM 112500), a condition characterized by the shortening of digits due to hypoplasia/aplasia of the middle phalanx. Indian Hedgehog signaling regulates the proliferation and differentiation of chondrocytes and is essential for endochondral bone formation. Analyses of activated IHH signaling in C3H10T1/2 cells showed that three BDA1-associated mutations (p.E95K, p.D100E and p.E131K) severely impaired the induction of targets such as Ptch1 and Gli1. However, this was not a complete loss of function, suggesting that these mutations may affect the interaction with the receptor PTCH1 or its partners, with an impact on the induction potency. From comparative microarray expression analyses and quantitative real-time PCR, we identified three additional targets, Sostdc1, Penk1 and Igfbp5, which were also severely affected. Penk1 and Igfbp5 were confirmed to be regulated by GLI1, while the induction of Sostdc1 by IHH is independent of GLI1. SOSTDC1 is a BMP antagonist, and altered BMP signaling is known to affect digit formation. The role of Penk1 and Igfbp5 in skeletogenesis is not known. However, we have shown that both Penk1 and Igfbp5 are expressed in the interzone region of the developing joint of mouse digits, providing another link for a role for IHH signaling in the formation of the distal digits. © 2009 by the University of Wrocław.
Persistent Identifierhttp://hdl.handle.net/10722/68276
ISSN
2015 Impact Factor: 1.753
2015 SCImago Journal Rankings: 0.788
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorGuo, Sen_HK
dc.contributor.authorZhou, Jen_HK
dc.contributor.authorGao, Ben_HK
dc.contributor.authorHu, Jen_HK
dc.contributor.authorWang, Hen_HK
dc.contributor.authorMeng, Jen_HK
dc.contributor.authorZhao, Xen_HK
dc.contributor.authorMa, Gen_HK
dc.contributor.authorLin, Cen_HK
dc.contributor.authorXiao, Yen_HK
dc.contributor.authorTang, Wen_HK
dc.contributor.authorZhu, Xen_HK
dc.contributor.authorCheah, KSEen_HK
dc.contributor.authorFeng, Gen_HK
dc.contributor.authorChan, Den_HK
dc.contributor.authorHe, Len_HK
dc.date.accessioned2010-09-06T06:03:02Z-
dc.date.available2010-09-06T06:03:02Z-
dc.date.issued2010en_HK
dc.identifier.citationCellular And Molecular Biology Letters, 2010, v. 15 n. 1, p. 153-176en_HK
dc.identifier.issn1425-8153en_HK
dc.identifier.urihttp://hdl.handle.net/10722/68276-
dc.description.abstractHeterozygous missense mutations in IHH result in Brachydactyly type A1 (BDA1; OMIM 112500), a condition characterized by the shortening of digits due to hypoplasia/aplasia of the middle phalanx. Indian Hedgehog signaling regulates the proliferation and differentiation of chondrocytes and is essential for endochondral bone formation. Analyses of activated IHH signaling in C3H10T1/2 cells showed that three BDA1-associated mutations (p.E95K, p.D100E and p.E131K) severely impaired the induction of targets such as Ptch1 and Gli1. However, this was not a complete loss of function, suggesting that these mutations may affect the interaction with the receptor PTCH1 or its partners, with an impact on the induction potency. From comparative microarray expression analyses and quantitative real-time PCR, we identified three additional targets, Sostdc1, Penk1 and Igfbp5, which were also severely affected. Penk1 and Igfbp5 were confirmed to be regulated by GLI1, while the induction of Sostdc1 by IHH is independent of GLI1. SOSTDC1 is a BMP antagonist, and altered BMP signaling is known to affect digit formation. The role of Penk1 and Igfbp5 in skeletogenesis is not known. However, we have shown that both Penk1 and Igfbp5 are expressed in the interzone region of the developing joint of mouse digits, providing another link for a role for IHH signaling in the formation of the distal digits. © 2009 by the University of Wrocław.en_HK
dc.languageengen_HK
dc.publisherVersita. The Journal's web site is located at http://www.cmbl.org.plen_HK
dc.relation.ispartofCellular and Molecular Biology Lettersen_HK
dc.subject.meshAnimalsen_HK
dc.subject.meshBone Morphogenetic Proteins - metabolismen_HK
dc.subject.meshCell Lineen_HK
dc.subject.meshChondrocytes - cytologyen_HK
dc.subject.meshEnkephalins - metabolismen_HK
dc.subject.meshHedgehog Proteins - genetics - metabolismen_HK
dc.subject.meshKruppel-Like Transcription Factors - metabolismen_HK
dc.subject.meshLimb Deformities, Congenital - geneticsen_HK
dc.subject.meshMiceen_HK
dc.subject.meshMicroarray Analysisen_HK
dc.subject.meshMutation, Missenseen_HK
dc.subject.meshPeptide Hormones - metabolismen_HK
dc.subject.meshProtein Precursors - metabolismen_HK
dc.subject.meshReceptors, Cell Surface - metabolismen_HK
dc.subject.meshRecombinant Proteins - genetics - metabolismen_HK
dc.subject.meshSignal Transductionen_HK
dc.titleMissense mutations in IHH impair Indian hedgehog signaling in C3H10T1/2 cells: Implications for brachydactyly type A1, and new targets for hedgehog signalingen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1425-8153&volume=15&issue=1&spage=153&epage=76&date=2009&atitle=Missense+mutations+in+IHH+impair+Indian+Hedgehog+signaling+in+C3H10T1/2+cells:+Implications+for+brachydactyly+type+A1,+and+new+targets+for+Hedgehog+signalingen_HK
dc.identifier.emailCheah, KSE:hrmbdkc@hku.hken_HK
dc.identifier.emailChan, D:chand@hkucc.hku.hken_HK
dc.identifier.authorityCheah, KSE=rp00342en_HK
dc.identifier.authorityChan, D=rp00540en_HK
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.2478/s11658-009-0040-2en_HK
dc.identifier.pmid20024692en_HK
dc.identifier.scopuseid_2-s2.0-76149118077en_HK
dc.identifier.hkuros169183en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-76149118077&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume15en_HK
dc.identifier.issue1en_HK
dc.identifier.spage153en_HK
dc.identifier.epage176en_HK
dc.identifier.isiWOS:000272968600011-
dc.publisher.placePolanden_HK
dc.identifier.scopusauthoridGuo, S=7403650670en_HK
dc.identifier.scopusauthoridZhou, J=7405551581en_HK
dc.identifier.scopusauthoridGao, B=24481275100en_HK
dc.identifier.scopusauthoridHu, J=25121188100en_HK
dc.identifier.scopusauthoridWang, H=9275335100en_HK
dc.identifier.scopusauthoridMeng, J=7202449855en_HK
dc.identifier.scopusauthoridZhao, X=7407576474en_HK
dc.identifier.scopusauthoridMa, G=54915525100en_HK
dc.identifier.scopusauthoridLin, C=15757729700en_HK
dc.identifier.scopusauthoridXiao, Y=35314160900en_HK
dc.identifier.scopusauthoridTang, W=7403430515en_HK
dc.identifier.scopusauthoridZhu, X=22137325700en_HK
dc.identifier.scopusauthoridCheah, KSE=35387746200en_HK
dc.identifier.scopusauthoridFeng, G=36698795100en_HK
dc.identifier.citeulike6451887-

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