The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

Ihh  -  Indian hedgehog

Mus musculus

Synonyms: HHG-2, IHH, Indian hedgehog protein
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of Ihh


High impact information on Ihh


Biological context of Ihh

  • The existence of such a repressor provides a window into the distant past, revealing that Shh and Ihh must once have shared responsibilities in establishing tissue boundaries and orchestrating vertebrate tissue morphogenesis [10].
  • The significance of these data extends far beyond the field of skeletal biology: they hint at the very real possibility that the endogenous Shh regulatory region contains a repressor designed to segregate the activity of Shh from Ihh [10].
  • Bone morphogenetic proteins (BMPs), another family of secreted factors regulating bone formation, have been implicated as potential interactors of the Ihh/PTHrP feedback loop [11].
  • In conclusion, the skeletal phenotype of Ihh(-/-) embryos represents the sum of disturbances in three separate cell populations, the chondrocytes, the osteoblasts and the vasculature, each of which is a direct target of hedgehog signaling [1].
  • Overexpression of Ihh in the cartilage elements of transgenic mice results in an upregulation of PTHrP expression and a delayed onset of hypertrophic differentiation [11].

Anatomical context of Ihh

  • Misexpression of Ihh prevents proliferating chondrocytes from initiating the hypertrophic differentiation process [9].
  • In this negative-feedback loop, Ihh inhibits hypertrophic differentiation by regulating the expression of Pthrp, which in turn acts directly on chondrocytes in the growth plate that express the PTH/PTHrP receptor [12].
  • In the ex vivo setting, Ihh(-/-) cells differentiate into osteoblasts and deposit a bony matrix, without benefit of exogenous hedgehog in the new environment [1].
  • Targeted inactivation of Ihh in mice allows ectopic branching of ventral pancreatic tissue resulting in an annulus that encircles the duodenum, a phenotype frequently observed in humans suffering from a rare disorder known as annular pancreas [13].
  • We consider that Ihh has a similar activity to Shh when expressed in the early Shh-responsive limb bud [14].

Associations of Ihh with chemical compounds


Physical interactions of Ihh


Regulatory relationships of Ihh

  • Thus BMP signaling does not act as a secondary signal of Ihh to induce PTHrP expression or to delay the onset of hypertrophic differentiation [11].
  • Adenoviral introduction of Runx2 in Runx2(-/-) chondrocyte cultures strongly induced Ihh expression [18].
  • Ihh controls cartilage development by antagonizing Gli3, but requires additional effectors to regulate osteoblast and vascular development [19].
  • Interestingly, Ihh is expressed at the tip of Shh mutant limbs and could account for formation of distal structures [20].
  • In the third model in which the PPR was disrupted in about 30% of columnar chondrocytes, Ihh action in the periarticular chondrocytes was upregulated because of ectopically differentiated hypertrophic chondrocytes that had lost PPR [21].
  • Dominant-negative Gli2 markedly inhibited Ihh-dependent osteoblast differentiation [22].

Other interactions of Ihh

  • A decrease in the domain of transcription of the chondrocyte markers Ihh and PTHrP (Pthlh) corresponded with a decrease in their transcripts in the proliferative and hypertrophic chondrocyte zones [23].
  • To determine whether Dbf maps to the Ihh locus, which is also on chromosome 1, we performed an interspecific backcross [14].
  • Normally, these cells surrounding the chondrogenic condensation are exposed to IHH, as evidenced by their expression of the hedgehog target genes, patched (Ptch) and Gli1 [1].
  • Although bmp6 was expressed, ihh transcripts were not found in primordia of intramembranous bones, nor in cells lining the future articular surfaces [24].
  • Rat Dhh mRNA was expressed in prostate, duodenum and dorsal root ganglia, while rat Ihh mRNA was expressed in cartilage [25].

Analytical, diagnostic and therapeutic context of Ihh

  • Hh-inactivating monoclonal antibodies or control antibodies were administered to mice that sustained a 50% intestinal resection. mRNA analyses of the preoperative ileum by quantitative real-time PCR revealed that Indian hedgehog was the most abundant Hh family member [26].
  • In the present study, we showed by Northern analysis and in situ hybridization that Smoothened (Smo), a key component in hedgehog signal transduction, was expressed in chondrocytes in both adult mice and mouse embryos at 16 days post-coitum in vivo, suggesting that Ihh directly acts on chondrocytes [27].
  • To reveal the possible function and interaction of these signaling systems we have started to analyze the expression patterns of signaling factors, antagonists, receptors and transducers of these pathways in forelimbs of mouse embryos and compared them to the expression of established markers including Ihh [28].
  • RT-PCR analysis of blastocyst outgrowth cultures demonstrates that whereas little or no Indian hedgehog message is present in blastocysts, significant levels appear upon subsequent days of culture, coincident with the emergence of parietal endoderm cells [17].
  • Using EC and ES cell culture to study early development: recent observations on Indian hedgehog and Bmps [29].


  1. Indian hedgehog synchronizes skeletal angiogenesis and perichondrial maturation with cartilage development. Colnot, C., de la Fuente, L., Huang, S., Hu, D., Lu, C., St-Jacques, B., Helms, J.A. Development (2005) [Pubmed]
  2. Hedgehog signal activation in gastric pit cell and in diffuse-type gastric cancer. Fukaya, M., Isohata, N., Ohta, H., Aoyagi, K., Ochiya, T., Saeki, N., Yanagihara, K., Nakanishi, Y., Taniguchi, H., Sakamoto, H., Shimoda, T., Nimura, Y., Yoshida, T., Sasaki, H. Gastroenterology (2006) [Pubmed]
  3. Indian hedgehog coordinates endochondral bone growth and morphogenesis via parathyroid hormone related-protein-dependent and -independent pathways. Karp, S.J., Schipani, E., St-Jacques, B., Hunzelman, J., Kronenberg, H., McMahon, A.P. Development (2000) [Pubmed]
  4. An in vivo comparative study of sonic, desert and Indian hedgehog reveals that hedgehog pathway activity regulates epidermal stem cell homeostasis. Adolphe, C., Narang, M., Ellis, T., Wicking, C., Kaur, P., Wainwright, B. Development (2004) [Pubmed]
  5. Developmental pathways in musculoskeletal neoplasia: involvement of the Indian Hedgehog-parathyroid hormone-related protein pathway. Tiet, T.D., Alman, B.A. Pediatr. Res. (2003) [Pubmed]
  6. Indian hedgehog is a major mediator of progesterone signaling in the mouse uterus. Lee, K., Jeong, J., Kwak, I., Yu, C.T., Lanske, B., Soegiarto, D.W., Toftgard, R., Tsai, M.J., Tsai, S., Lydon, J.P., Demayo, F.J. Nat. Genet. (2006) [Pubmed]
  7. Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R asymmetry by the mouse node. Zhang, X.M., Ramalho-Santos, M., McMahon, A.P. Cell (2001) [Pubmed]
  8. Mice lacking link protein develop dwarfism and craniofacial abnormalities. Watanabe, H., Yamada, Y. Nat. Genet. (1999) [Pubmed]
  9. Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein. Vortkamp, A., Lee, K., Lanske, B., Segre, G.V., Kronenberg, H.M., Tabin, C.J. Science (1996) [Pubmed]
  10. The fickle finger of fate. de la Fuente, L., Helms, J.A. J. Clin. Invest. (2005) [Pubmed]
  11. BMP and Ihh/PTHrP signaling interact to coordinate chondrocyte proliferation and differentiation. Minina, E., Wenzel, H.M., Kreschel, C., Karp, S., Gaffield, W., McMahon, A.P., Vortkamp, A. Development (2001) [Pubmed]
  12. TGFbeta2 mediates the effects of hedgehog on hypertrophic differentiation and PTHrP expression. Alvarez, J., Sohn, P., Zeng, X., Doetschman, T., Robbins, D.J., Serra, R. Development (2002) [Pubmed]
  13. Regulation of pancreas development by hedgehog signaling. Hebrok, M., Kim, S.K., St Jacques, B., McMahon, A.P., Melton, D.A. Development (2000) [Pubmed]
  14. Evidence that preaxial polydactyly in the Doublefoot mutant is due to ectopic Indian Hedgehog signaling. Yang, Y., Guillot, P., Boyd, Y., Lyon, M.F., McMahon, A.P. Development (1998) [Pubmed]
  15. Indian hedgehog as a progesterone-responsive factor mediating epithelial-mesenchymal interactions in the mouse uterus. Matsumoto, H., Zhao, X., Das, S.K., Hogan, B.L., Dey, S.K. Dev. Biol. (2002) [Pubmed]
  16. Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification. Koziel, L., Kunath, M., Kelly, O.G., Vortkamp, A. Dev. Cell (2004) [Pubmed]
  17. A role for Indian hedgehog in extraembryonic endoderm differentiation in F9 cells and the early mouse embryo. Becker, S., Wang, Z.J., Massey, H., Arauz, A., Labosky, P., Hammerschmidt, M., St-Jacques, B., Bumcrot, D., McMahon, A., Grabel, L. Dev. Biol. (1997) [Pubmed]
  18. Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog. Yoshida, C.A., Yamamoto, H., Fujita, T., Furuichi, T., Ito, K., Inoue, K., Yamana, K., Zanma, A., Takada, K., Ito, Y., Komori, T. Genes Dev. (2004) [Pubmed]
  19. Ihh controls cartilage development by antagonizing Gli3, but requires additional effectors to regulate osteoblast and vascular development. Hilton, M.J., Tu, X., Cook, J., Hu, H., Long, F. Development (2005) [Pubmed]
  20. Some distal limb structures develop in mice lacking Sonic hedgehog signaling. Kraus, P., Fraidenraich, D., Loomis, C.A. Mech. Dev. (2001) [Pubmed]
  21. PTHrP and Indian hedgehog control differentiation of growth plate chondrocytes at multiple steps. Kobayashi, T., Chung, U.I., Schipani, E., Starbuck, M., Karsenty, G., Katagiri, T., Goad, D.L., Lanske, B., Kronenberg, H.M. Development (2002) [Pubmed]
  22. Ihh/Gli2 signaling promotes osteoblast differentiation by regulating Runx2 expression and function. Shimoyama, A., Wada, M., Ikeda, F., Hata, K., Matsubara, T., Nifuji, A., Noda, M., Amano, K., Yamaguchi, A., Nishimura, R., Yoneda, T. Mol. Biol. Cell (2007) [Pubmed]
  23. The IIIc alternative of Fgfr2 is a positive regulator of bone formation. Eswarakumar, V.P., Monsonego-Ornan, E., Pines, M., Antonopoulou, I., Morriss-Kay, G.M., Lonai, P. Development (2002) [Pubmed]
  24. Expression of indian hedgehog, bone morphogenetic protein 6 and gli during skeletal morphogenesis. Iwasaki, M., Le, A.X., Helms, J.A. Mech. Dev. (1997) [Pubmed]
  25. Identification and characterization of rat Desert hedgehog and Indian hedgehog genes in silico. Katoh, Y., Katoh, M. Int. J. Oncol. (2005) [Pubmed]
  26. Increased apoptosis and accelerated epithelial migration following inhibition of hedgehog signaling in adaptive small bowel postresection. Tang, Y., Swietlicki, E.A., Jiang, S., Buhman, K.K., Davidson, N.O., Burkly, L.C., Levin, M.S., Rubin, D.C. Am. J. Physiol. Gastrointest. Liver Physiol. (2006) [Pubmed]
  27. Indian hedgehog in the late-phase differentiation in mouse chondrogenic EC cells, ATDC5: upregulation of type X collagen and osteoprotegerin ligand mRNAs. Akiyama, H., Shigeno, C., Iyama, K., Ito, H., Hiraki, Y., Konishi, J., Nakamura, T. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  28. Expression of Fgf and Tgfbeta signaling related genes during embryonic endochondral ossification. Minina, E., Schneider, S., Rosowski, M., Lauster, R., Vortkamp, A. Gene Expr. Patterns (2005) [Pubmed]
  29. Using EC and ES cell culture to study early development: recent observations on Indian hedgehog and Bmps. Grabel, L., Becker, S., Lock, L., Maye, P., Zanders, T. Int. J. Dev. Biol. (1998) [Pubmed]
WikiGenes - Universities