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Gene Review

Shh  -  sonic hedgehog

Rattus norvegicus

Synonyms: SHH, Sonic hedgehog protein, Vhh-1
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Disease relevance of Shh

  • We found that the G12 family of heterotrimeric G proteins and the small GTPase RhoA are involved in Shh/Smo-mediated cellular responses, including stimulation of target gene promoter and inhibition of neurite outgrowth of neuroblastoma cells [1].
  • Surprisingly, in the culture experiments, the fistula tract was induced to branch by exogenous Shh [2].
  • In the presence of testosterone, inhibition of SHH-signalling accelerated the canalisation of prostatic epithelial ducts and resulted in ducts that showed morphological similarities to cribiform prostatic intraepithelial neoplasia (PIN) [3].
  • We investigated whether intramyocardial gene transfer of naked DNA encoding human Shh (phShh) could promote a favorable effect on recovery from acute and chronic myocardial ischemia in adult animals, not only by promoting neovascularization, but by broader effects, consistent with the role of this morphogen in embryogenesis [4].
  • Thus Shh may have therapeutic value as a protective agent in neurodegenerative disease [5].

High impact information on Shh

  • Sonic hedgehog (Shh) is a crucial regulator of organ development during embryogenesis [4].
  • Shh gene transfer also enhanced the contribution of bone marrow-derived endothelial progenitor cells to myocardial neovascularization [4].
  • After Shh gene transfer, the hedgehog pathway was upregulated in mammalian fibroblasts and cardiomyocytes [4].
  • These data suggest that Shh gene therapy may have considerable therapeutic potential in individuals with acute and chronic myocardial ischemia by triggering expression of multiple trophic factors and engendering tissue repair in the adult heart [4].
  • Here we provide evidence for a freely diffusible form of Shh (s-ShhNp) that is cholesterol modified, multimeric and biologically potent [6].

Chemical compound and disease context of Shh

  • Direct intracerebral administration of sonic hedgehog (SHH) reduces 6-OHDA and MPTP toxicity to nigral dopaminergic cells in rats and primates [7].

Biological context of Shh

  • Short-term VP and LP cultures with FgfR antagonist PD173074 and Mek inhibitor U0126 identified epithelial Shh and Hoxb13 up-regulation by androgens to be Fgf10-dependent [8].
  • This is the first evidence that alveolar fluid distension is an organizing principle for PTHrP signaling down-regulation of the Shh/Wnt/betacatenin pathway [9].
  • Our results showed that in normal controls the expression of Shh increased with advancing gestation, peaked in the late pseudoglandular stage, and declined thereafter [10].
  • We used an embryonic, tongue organ culture system that retains temporal, spatial, and molecular characteristics of in vivo taste papilla morphogenesis and patterning to study the role of Shh in taste papilla development [11].
  • Shh selectively triggered mitosis of OP but not neuronal progenitors and enhanced growth of neonatal OP [12].

Anatomical context of Shh

  • Lung development depends on endodermal Sonic Hedgehog (Shh) signaling to mesodermal Wingless/int/beta catenin (Wnt/betacatenin), followed by parathyroid hormone-related protein (PTHrP) signaling from endoderm to mesoderm [9].
  • AMY cells expressed approximately 900-fold elevation of the Hh ligand, Indian Hh (Ihh), compared with normal esophageal epithelium, whereas expression of another Hh ligand, Sonic Hh (Shh), was not detected [13].
  • This work identifies Shh as a regulator of adult hippocampal neural stem cells [14].
  • We found high expression of the Shh receptor Patched in both the adult rat hippocampus and neural progenitor cells isolated from this region [14].
  • This uncoupling of tyrosine hydroxylase expression from other dopaminergic markers suggests that the midbrain dopaminergic identity is dictated by a combination of pan-dopaminergic (e.g., Shh/FGF-8) and region-specific (Nurr1) mechanisms [15].

Associations of Shh with chemical compounds

  • PACAP markedly inhibited Shh-induced thymidine incorporation by 50 and 85% in rat and mouse GNPs, respectively, but did not significantly affect the stimulation induced by other mitogens [16].
  • Prostatic budding was induced in response to testosterone in Shh null mouse urogenital sinus (UGS) explants grown in vitro and in rat UGS explants cultured with cyclopamine, suggesting that SHH-signalling is not critical for prostatic induction [3].
  • In conclusion, we show that SHH-signalling is not essential for prostatic induction, but is important for prostatic growth, branching, and proliferation, and that androgen-stimulated growth in the absence of signalling from the SHH pathway results in aberrant epithelial differentiation [3].
  • Neonatal exposure to high-dose estradiol suppressed Shh, ptc, gli1, and gli3 expressions and concomitantly blocked ductal branching in the dorsal and lateral prostate lobes specifically [17].
  • At the early-somite stage we observed a reduction of Shh signaling in AY9944 treated embryos, resulting in the definition of a narrower ventral domain [18].

Physical interactions of Shh


Regulatory relationships of Shh

  • In the postnatal cerebellum, Shh expressed by Purkinje cells may act on its target receptor complex localized in the external germinative layer to activate Gli1 [19].
  • CONCLUSIONS: Exogenous Shh administration promotes nestin-positive cell proliferation after SCI in adult rodents [21].

Other interactions of Shh

  • The results suggest that TGF-beta is required for survival of mesencephalic dopaminergic neurons acting in cooperation with Shh and FGF8 [22].
  • Transcripts for the putative Shh-receptor genes patched (Ptc) and smoothened (Smo) are expressed by embryonic, postnatal, and adult progenitor cells, suggesting that Shh can act directly on these cells [23].
  • We suggest that the posterior skeletal elements may be fully formed owing to Shh expression, but the anterior skeletal elements may be underdeveloped owing to an intense reduction of Bmp4 expression in the anterior mesenchyme, causing hypoplasia of the tibial ray [24].
  • To know reasons for perturbed progenitor domain formation in Pax6 mutant, we examined expression patterns of Shh signalling molecules and states of cell death and cell proliferation [25].
  • Shh was similarly expressed in the floor plate of the mutant hindbrain, while the expressions of Ptc1, Gli1 and Gli2 were altered only in the progenitor domains for the motoneurones [25].

Analytical, diagnostic and therapeutic context of Shh


  1. The G12 family of heterotrimeric G proteins and Rho GTPase mediate Sonic hedgehog signalling. Kasai, K., Takahashi, M., Osumi, N., Sinnarajah, S., Takeo, T., Ikeda, H., Kehrl, J.H., Itoh, G., Arnheiter, H. Genes Cells (2004) [Pubmed]
  2. Defective sonic hedgehog signaling in esophageal atresia with tracheoesophageal fistula. Spilde, T.L., Bhatia, A.M., Mehta, S., Ostlie, D.J., Hembree, M.J., Preuett, B.L., Prasadan, K., Li, Z., Snyder, C.L., Gittes, G.K. Surgery (2003) [Pubmed]
  3. Sonic hedgehog regulates prostatic growth and epithelial differentiation. Freestone, S.H., Marker, P., Grace, O.C., Tomlinson, D.C., Cunha, G.R., Harnden, P., Thomson, A.A. Dev. Biol. (2003) [Pubmed]
  4. Sonic hedgehog myocardial gene therapy: tissue repair through transient reconstitution of embryonic signaling. Kusano, K.F., Pola, R., Murayama, T., Curry, C., Kawamoto, A., Iwakura, A., Shintani, S., Ii, M., Asai, J., Tkebuchava, T., Thorne, T., Takenaka, H., Aikawa, R., Goukassian, D., von Samson, P., Hamada, H., Yoon, Y.S., Silver, M., Eaton, E., Ma, H., Heyd, L., Kearney, M., Munger, W., Porter, J.A., Kishore, R., Losordo, D.W. Nat. Med. (2005) [Pubmed]
  5. Sonic hedgehog promotes the survival of specific CNS neuron populations and protects these cells from toxic insult In vitro. Miao, N., Wang, M., Ott, J.A., D'Alessandro, J.S., Woolf, T.M., Bumcrot, D.A., Mahanthappa, N.K., Pang, K. J. Neurosci. (1997) [Pubmed]
  6. A freely diffusible form of Sonic hedgehog mediates long-range signalling. Zeng, X., Goetz, J.A., Suber, L.M., Scott, W.J., Schreiner, C.M., Robbins, D.J. Nature (2001) [Pubmed]
  7. Sonic hedgehog delivered by an adeno-associated virus protects dopaminergic neurones against 6-OHDA toxicity in the rat. Dass, B., Iravani, M.M., Huang, C., Barsoum, J., Engber, T.M., Galdes, A., Jenner, P. Journal of neural transmission (Vienna, Austria : 1996) (2005) [Pubmed]
  8. Androgen regulation of prostate morphoregulatory gene expression: Fgf10-dependent and -independent pathways. Pu, Y., Huang, L., Birch, L., Prins, G.S. Endocrinology (2007) [Pubmed]
  9. Up-Regulation of Fetal Rat Lung Parathyroid Hormone-Related Protein Gene Regulatory Network Down-Regulates the Sonic Hedgehog/Wnt/{beta}catenin Gene Regulatory Network. Torday, J.S., Rehan, V.K. Pediatr. Res. (2006) [Pubmed]
  10. Down-regulation of sonic hedgehog expression in pulmonary hypoplasia is associated with congenital diaphragmatic hernia. Unger, S., Copland, I., Tibboel, D., Post, M. Am. J. Pathol. (2003) [Pubmed]
  11. Cyclopamine and jervine in embryonic rat tongue cultures demonstrate a role for Shh signaling in taste papilla development and patterning: fungiform papillae double in number and form in novel locations in dorsal lingual epithelium. Mistretta, C.M., Liu, H.X., Gaffield, W., MacCallum, D.K. Dev. Biol. (2003) [Pubmed]
  12. Sonic hedgehog is a potent inducer of rat oligodendrocyte development from cortical precursors in vitro. Murray, K., Calaora, V., Rottkamp, C., Guicherit, O., Dubois-Dalcq, M. Mol. Cell. Neurosci. (2002) [Pubmed]
  13. Epidermal growth factor receptor and hedgehog signaling pathways are active in esophageal cancer cells from rat reflux model. Sui, G., Bonde, P., Dhara, S., Broor, A., Wang, J., Marti, G., Feldmann, G., Duncan, M., Montgomery, E., Maitra, A., Harmon, J.W. J. Surg. Res. (2006) [Pubmed]
  14. Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Lai, K., Kaspar, B.K., Gage, F.H., Schaffer, D.V. Nat. Neurosci. (2003) [Pubmed]
  15. Nurr1, an orphan nuclear receptor, is a transcriptional activator of endogenous tyrosine hydroxylase in neural progenitor cells derived from the adult brain. Sakurada, K., Ohshima-Sakurada, M., Palmer, T.D., Gage, F.H. Development (1999) [Pubmed]
  16. Pituitary adenylate cyclase-activating polypeptide and sonic hedgehog interact to control cerebellar granule precursor cell proliferation. Nicot, A., Lelièvre, V., Tam, J., Waschek, J.A., DiCicco-Bloom, E. J. Neurosci. (2002) [Pubmed]
  17. Sonic hedgehog-patched Gli signaling in the developing rat prostate gland: lobe-specific suppression by neonatal estrogens reduces ductal growth and branching. Pu, Y., Huang, L., Prins, G.S. Dev. Biol. (2004) [Pubmed]
  18. Expression of Sonic Hedgehog downstream genes is modified in rat embryos exposed in utero to a distal inhibitor of cholesterol biosynthesis. Gofflot, F., Gaoua, W., Bourguignon, L., Roux, C., Picard, J.J. Dev. Dyn. (2001) [Pubmed]
  19. Sonic Hedgehog signalling in the developing and adult brain. Charytoniuk, D., Porcel, B., Rodríguez Gomez, J., Faure, H., Ruat, M., Traiffort, E. J. Physiol. Paris (2002) [Pubmed]
  20. Megalin functions as an endocytic sonic hedgehog receptor. McCarthy, R.A., Barth, J.L., Chintalapudi, M.R., Knaak, C., Argraves, W.S. J. Biol. Chem. (2002) [Pubmed]
  21. Sonic hedgehog-induced neural precursor proliferation after adult rodent spinal cord injury. Bambakidis, N.C., Wang, R.Z., Franic, L., Miller, R.H. J. Neurosurg. (2003) [Pubmed]
  22. TGF-beta promotes survival on mesencephalic dopaminergic neurons in cooperation with Shh and FGF-8. Roussa, E., Farkas, L.M., Krieglstein, K. Neurobiol. Dis. (2004) [Pubmed]
  23. Sonic hedgehog and BMP2 exert opposing actions on proliferation and differentiation of embryonic neural progenitor cells. Zhu, G., Mehler, M.F., Zhao, J., Yu Yung, S., Kessler, J.A. Dev. Biol. (1999) [Pubmed]
  24. Developmental abnormalities in rat embryos leading to tibial ray deficiencies induced by busulfan. Otsuji, M., Takahara, M., Naruse, T., Guan, D., Harada, M., Zhe, P., Takagi, M., Ogino, T. Birth defects research. Part A, Clinical and molecular teratology. (2005) [Pubmed]
  25. Pax6 regulates specification of ventral neurone subtypes in the hindbrain by establishing progenitor domains. Takahashi, M., Osumi, N. Development (2002) [Pubmed]
  26. Sonic hedgehog cascade is required for penile postnatal morphogenesis, differentiation, and adult homeostasis. Podlasek, C.A., Zelner, D.J., Jiang, H.B., Tang, Y., Houston, J., McKenna, K.E., McVary, K.T. Biol. Reprod. (2003) [Pubmed]
  27. The upregulated expression of sonic hedgehog in motor neurons after rat facial nerve axotomy. Akazawa, C., Tsuzuki, H., Nakamura, Y., Sasaki, Y., Ohsaki, K., Nakamura, S., Arakawa, Y., Kohsaka, S. J. Neurosci. (2004) [Pubmed]
  28. Differential expression of sonic hedgehog immunoreactivity during lesion evolution in autoimmune encephalomyelitis. Seifert, T., Bauer, J., Weissert, R., Fazekas, F., Storch, M.K. J. Neuropathol. Exp. Neurol. (2005) [Pubmed]
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