Jianxin Hu

Publications (7)88.73 Total impact

• Article: Indian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels.

  Gang Ma, Jiang Yu, Yue Xiao, Danny Chan, Bo Gao, Jianxin Hu, Yongxing He, Shengzhen Guo, Jian Zhou, Lingling Zhang, Linghan Gao, Wenjuan Zhang, Yan Kang, Kathryn S E Cheah, Guoyin Feng, Xizhi Guo, Yujiong Wang, Cong-zhao Zhou, Lin He
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  ABSTRACT: Brachydactyly type A1 (BDA1), the first recorded Mendelian autosomal dominant disorder in humans, is characterized by a shortening or absence of the middle phalanges. Heterozygous missense mutations in the Indian Hedgehog (IHH) gene have been identified as a cause of BDA1; however, the biochemical consequences of these mutations are unclear. In this paper, we analyzed three BDA1 mutations (E95K, D100E, and E131K) in the N-terminal fragment of Indian Hedgehog (IhhN). Structural analysis showed that the E95K mutation changes a negatively charged area to a positively charged area in a calcium-binding groove, and that the D100E mutation changes the local tertiary structure. Furthermore, we showed that the E95K and D100E mutations led to a temperature-sensitive and calcium-dependent instability of IhhN, which might contribute to an enhanced intracellular degradation of the mutant proteins via the lysosome. Notably, all three mutations affected Hh binding to the receptor Patched1 (PTC1), reducing its capacity to induce cellular differentiation. We propose that these are common features of the mutations that cause BDA1, affecting the Hh tertiary structure, intracellular fate, binding to the receptor/partners, and binding to extracellular components. The combination of these features alters signaling capacity and range, but the impact is likely to be variable and mutation-dependent. The potential variation in the signaling range is characterized by an enhanced interaction with heparan sulfate for IHH with the E95K mutation, but not the E131K mutation. Taken together, our results suggest that these IHH mutations affect Hh signaling at multiple levels, causing abnormal bone development and abnormal digit formation.
  Cell Research 05/2011; 21(9):1343-57. · 8.19 Impact Factor
• Article: Missense mutations in IHH impair Indian Hedgehog signaling in C3H10T1/2 cells: Implications for brachydactyly type A1, and new targets for Hedgehog signaling.

  Shengzhen Guo, Jian Zhou, Bo Gao, Jianxin Hu, Hongsheng Wang, Junwei Meng, Xinzhi Zhao, Gang Ma, Chuwen Lin, Yue Xiao, Wei Tang, Xuming Zhu, Kathryn S E Cheah, Guoying Feng, Danny Chan, Lin He
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  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.
  Cellular & Molecular Biology Letters 01/2010; 15(1):153-76. · 1.50 Impact Factor
• Article: Haplotype analysis confirms association of the serotonin transporter (5-HTT) gene with schizophrenia in the Han Chinese population.

  Chuwen Lin, Wei Tang, Jianxin Hu, Linhan Gao, Ke Huang, Yifeng Xu, Guang He, Peiji Liang, Guoyin Feng, Lin He, Yongyong Shi
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  ABSTRACT: Serotonin transmission has long been suspected as being involved in the pathogenesis of schizophrenia. 5-HTT is a promising candidate gene for schizophrenia due to its critical role in regulating serotonin transmission and role in the mechanism of the atypical antipsychotic drugs. A common polymorphism STin2 VNTR in the 5-HTT gene has been extensively investigated in the genetic association studies, but the results are conflicting. Meanwhile, the SNPs of the 5-HTT gene have been much less explored. We therefore conducted a case-control study of the association between STin2 VNTR and three tagging SNPs in 5-HTT and schizophrenia in the Han Chinese population based on a cohort of 329 schizophrenic patients and 288 control subjects. No association was found in the single locus, but haplotype-based analyses revealed significant association between two haplotypes with schizophrenia even after Bonferroni correction (P=0.00000538 and 0.011).
  Neuroscience Letters 05/2009; 453(3):210-3. · 2.11 Impact Factor
• Source

  Available from: Sigmar Stricker

  Article: A mutation in Ihh that causes digit abnormalities alters its signalling capacity and range.

  Bo Gao, Jianxin Hu, Sigmar Stricker, Martin Cheung, Gang Ma, Kit Fong Law, Florian Witte, James Briscoe, Stefan Mundlos, Lin He, Kathryn S E Cheah, Danny Chan
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  ABSTRACT: Brachydactyly type A1 (BDA1) was the first recorded disorder of the autosomal dominant Mendelian trait in humans, characterized by shortened or absent middle phalanges in digits. It is associated with heterozygous missense mutations in indian hedgehog (IHH). Hedgehog proteins are important morphogens for a wide range of developmental processes. The capacity and range of signalling is thought to be regulated by its interaction with the receptor PTCH1 and antagonist HIP1. Here we show that a BDA1 mutation (E95K) in Ihh impairs the interaction of IHH with PTCH1 and HIP1. This is consistent with a recent paper showing that BDA1 mutations cluster in a calcium-binding site essential for the interaction with its receptor and cell-surface partners. Furthermore, we show that in a mouse model that recapitulates the E95K mutation, there is a change in the potency and range of signalling. The mice have digit abnormalities consistent with the human disorder.
  Nature 04/2009; 458(7242):1196-200. · 36.28 Impact Factor
• Source

  Available from: Stefan Mundlos

  Article: A mutation in Ihh that causes digit abnormalities alters its signalling capacity and range

  Bo Gao, Jianxin Hu, Sigmar Stricker, Martin Cheung, Gang Ma, Kit Fong Law, Florian Witte, James Briscoe, Stefan Mundlos, Lin He, Kathryn S. E. Cheah, Danny Chan
  [show abstract] [hide abstract]
  ABSTRACT: Brachydactyly type A1 (BDA1) was the first recorded disorder of the autosomal dominant Mendelian trait in humans, characterized by shortened or absent middle phalanges in digits. It is associated with heterozygous missense mutations in indian hedgehog (
  Nature 02/2009; 458(7242):1196-1200. · 36.28 Impact Factor
• Article: Patterning mechanisms controlling digit development.

  Jianxin Hu, Lin He
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  ABSTRACT: Vertebrate digits are essential structures for movement, feeding and communication. Specialized regions of the developing limb bud including the zone of polarizing activity (ZPA), the apical ectodermal ridge (AER), and the non-ridge ectoderm regulate the patterning of digits. Although a series of signaling molecules have been characterized as patterning signals from the organizing centers, the delicate cellular and molecular mechanisms that interpret how these patterning signals control the detailed digit anatomy remain unclear. Recent studies from model organisms and human hand malformations provide new insights into the mechanisms regulating this process. Here, we review the current understanding of the genetic networks governing digit morphogenesis.
  Journal of Genetics and Genomics 10/2008; 35(9):517-24. · 1.88 Impact Factor
• Article: IHH and FGF8 coregulate elongation of digit primordia.

  Jian Zhou, Junwei Meng, Shengzhen Guo, Bo Gao, Gang Ma, Xuming Zhu, Jianxin Hu, Yue Xiao, Chuwen Lin, Hongsheng Wang, Lusheng Ding, Guoyin Feng, Xizhi Guo, Lin He
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  ABSTRACT: In the developing limb bud, digit pattern arises from anterior-posterior (A-P) positional information which is provided by the concentration gradient of SHH. However, the mechanisms of translating early asymmetry into morphological form are still unclear. Here, we examined the ability of IHH and FGF8 signaling to regulate digital chondrogenesis, by implanting protein-loaded beads in the interdigital space singly and in combination. We found that IHH protein induced an elongated digit and that FGF8 protein blocked the terminal phalange formation. Molecular marker analysis showed that IHH expanded Sox9 expression in mesenchymal cells possibly through up-regulated FGF8 expression. Application of both IHH and FGF8 protein induced a large terminal phalange. These results suggest that both enhanced IHH and FGF8 signaling are required for the development of additional cartilage element in limbs. IHH and FGF8 maybe play different roles and act synergistically to promote chondrogenesis during digit primordia elongation.
  Biochemical and Biophysical Research Communications 12/2007; 363(3):513-8. · 2.48 Impact Factor