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

Cellular & Molecular Biology Letters

Guoying Feng¹  Lin He⁶  Shengzhen Guo⁴  Xinzhi Zhao⁵  Bo Gao⁴  Danny Chan²  Jian Zhou⁵  Chuwen Lin⁵  Junwei Meng⁵  Yue Xiao⁵  Kathryn S.E. Cheah³  Jianxin Hu⁴  Wei Tang⁵  Gang Ma⁵  Hongsheng Wang⁵  Xuming Zhu⁵ 

[1]Shanghai Institutes of Mental Health, Shanghai, China$$

[2]Department of Biochemistry, The University of Hong Kong, Pokfulam, Hong Kong, China$$Department of Biochemistry, The University of Hong Kong, Pokfulam, Hong Kong, China$$

[3]Department of Biochemistry, The University of Hong Kong, Pokfulam, Hong Kong, China$$

[4]Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China$$Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China$$Department of Biochemistry, The University of Hong Kong, Pokfulam, Hong Kong, China$$

[5]Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China$$Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China$$

[6]Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China$$Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China$$Institutes of Biomedical Sciences, Fudan University, Shanghai, PR China$$Bio-X Center, Shanghai Jiao Tong University, Shanghai, China$$

关键词: Indian Hedgehog;    Brachydactyly type A1;    Microarray;    EMSA;   

DOI  :  10.2478/s11658-009-0040-2

学科分类：分子生物学，细胞生物学和基因

来源: Uniwersytet Wroclawski * Wydzial Biotechnologii / University of Wroclaw, Faculty of Biotechnology

【 摘 要 】

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.

【 授权许可】

Unknown