title: Missense mutations in IHH impair Indian Hedgehog signaling in C3H10T1/2 cells: Implications for brachydactyly type A1, and new targets for Hedgehog signaling.
abstract: Heterozygous 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.
authors.affiliation: Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
authors.forename: Shengzhen
authors.initials: S
authors.lastname: Guo
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.forename: Bo
authors.initials: B
authors.lastname: Gao
authors.forename: Jianxin
authors.initials: J
authors.lastname: Hu
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Wang
authors.forename: Junwei
authors.initials: J
authors.lastname: Meng
authors.forename: Xinzhi
authors.initials: X
authors.lastname: Zhao
authors.forename: Gang
authors.initials: G
authors.lastname: Ma
authors.forename: Chuwen
authors.initials: C
authors.lastname: Lin
authors.forename: Yue
authors.initials: Y
authors.lastname: Xiao
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.forename: Xuming
authors.initials: X
authors.lastname: Zhu
authors.forename: Kathryn S E
authors.initials: KS
authors.lastname: Cheah
authors.forename: Guoying
authors.initials: G
authors.lastname: Feng
authors.forename: Danny
authors.initials: D
authors.lastname: Chan
authors.forename: Lin
authors.initials: L
authors.lastname: He
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002460:Cell Line; D019902:Chondrocytes / Q000166:cytology; D004745:Enkephalins / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D017880:Limb Deformities, Congenital / Q000235:genetics; D051379:Mice; D046228:Microarray Analysis; D020125:Mutation, Missense; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D036361:Peptide Hormones / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000071676:Zinc Finger Protein GLI1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D004745:Enkephalins; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; C121388:Insl5 protein, mouse; D051741:Kruppel-Like Transcription Factors; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D036361:Peptide Hormones; D011498:Protein Precursors; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C483887:Sostdc1 protein, mouse; D000071676:Zinc Finger Protein GLI1; C514061:ihh protein, mouse; C033660:preproenkephalin