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Gene Review

Shh  -  sonic hedgehog

Mus musculus

Synonyms: 9530036O11Rik, Dsh, HHG-1, Hhg1, Hx, ...
 
 
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Disease relevance of Shh

 

High impact information on Shh

  • Finally, by fate mapping Shh-responding cells in Gli2 and Gli3 mutant limbs, we demonstrate that a specific level of positive Hh signaling is not required to specify digit identities [7].
  • Our results show that all posterior limb mesenchyme cells, as well as the ectoderm, respond to Shh from the ZPA and become the bone, muscle, and skin of the posterior limb [7].
  • The zone of polarizing activity (ZPA) in the posterior limb bud produces Sonic Hedgehog (Shh) protein, which plays a critical role in establishing distinct fates along the anterior-posterior axis [8].
  • Embryonic fibroblasts lacking mDispA respond normally to exogenously provided Sonic hedgehog (Shh) signal, but are impaired in stimulation of other responding cells when expressing Shh [9].
  • Smo and Shh/Ihh compound mutants have identical phenotypes: embryos fail to turn, arresting at somite stages with a small, linear heart tube, an open gut and cyclopia [10].
 

Chemical compound and disease context of Shh

  • The authors aimed to study the temporal and spatial pattern of expression of Shh and its receptor Ptc1 during the development of the anterior foregut and to test the hypothesis that the Shh expression pattern is disturbed during the development of oesophageal atresia (OA) and tracheo-oesophageal fistula (TOF) in Adriamycin-treated mouse embryos [11].
 

Biological context of Shh

  • Whereas otic induction proceeds normally in Shh(-/-) embryos, morphogenesis of the inner ear is greatly perturbed by midgestation [12].
  • The inversion results in almost complete downregulation of Shh expression during E9.5-E12.5, explaining the homozygous phenotype [13].
  • We mapped Dsh to chromosome 5 in a region containing Shh and were able to demonstrate an inversion comprising 11.7 Mb [13].
  • In this model it is not clear which aspects of the phenotype are the result of the direct action of Shh on a target tissue and which are indirect effects due to deficiencies in reciprocal signalings between the epithelial and mesenchymal components [14].
  • Gli2(-/-)Gli3(-/-) embryos exhibit a severe loss of sclerotomal gene expression, and somitic mesoderm from these embryos cannot activate sclerotomal genes in response to exogenous Shh [15].
 

Anatomical context of Shh

 

Associations of Shh with chemical compounds

 

Physical interactions of Shh

  • Hoxd-12 can bind to and transactivate the Shh promoter in vitro [24].
  • A Gli-binding site located within the ES enhancer is required for enhancer activation by Shh signaling in transfected 3T3 cells and in epaxial somite progenitors in transgenic embryos [25].
  • Mutational analysis revealed that the homeodomain and Foxa binding sites are each required for activation of the Shh floor plate enhancer, whereas the Tbx site was required for repression in regions of the CNS where Shh is not normally expressed [26].
  • We show that Shh directly binds to laminin and that laminin-Shh induced cell proliferation is dependent on beta1 integrin expression in GCPs [27].
  • After translation, Shh autoproteolyzes and covalently attaches cholesterol to the newly formed carboxyl terminus, a modification crucial for normal Shh signaling [28].
 

Co-localisations of Shh

  • Caspase3 whole mount immunostaining revealed that cholesterol biosynthesis colocalizes with apoptotic regions that are targets of the morphogenic signal Sonic hedgehog [29].
 

Regulatory relationships of Shh

  • Thus Ptc appears to be essential for repression of genes that are locally activated by Shh [4].
  • In addition, we find that FGF4 beads induce rapidly the expression of Fgf3 in dental mesenchyme and that both epithelial and mesenchymal FGF proteins induce the delayed expression of Shh in the epithelium [30].
  • We show here that Shh is expressed normally in Dbf mutants [31].
  • Sonic hedgehog signaling regulates Gli3 processing, mesenchymal proliferation, and differentiation during mouse lung organogenesis [32].
  • Wnt5a regulates Shh and Fgf10 signaling during lung development [33].
  • By examining embryonic mouse tongues in culture we determined that activation of Wnt/beta-catenin signaling up-regulates Shh expression [34].
  • We show that Gas1 and Cdo cooperate to promote Shh signaling during neural tube patterning, craniofacial, and vertebral development [35].
 

Other interactions of Shh

  • Here we show that dorsal ectoderm is required together with FGF4 to maintain Shh expression [16].
  • Moreover, loss of Ptc or overexpression of Shh cannot be the sole causes of Gli1 induction and sporadic BCC formation, as they do not occur consistently [36].
  • The Sonic Hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis [37].
  • Interplays of Gli2 and Gli3 and their requirement in mediating Shh-dependent sclerotome induction [15].
  • We consider that Ihh has a similar activity to Shh when expressed in the early Shh-responsive limb bud [31].
 

Analytical, diagnostic and therapeutic context of Shh

References

  1. Inhibition of epithelial ductal branching in the prostate by sonic hedgehog is indirectly mediated by stromal cells. Wang, B.E., Shou, J., Ross, S., Koeppen, H., De Sauvage, F.J., Gao, W.Q. J. Biol. Chem. (2003) [Pubmed]
  2. Sonic hedgehog is essential for first pharyngeal arch development. Yamagishi, C., Yamagishi, H., Maeda, J., Tsuchihashi, T., Ivey, K., Hu, T., Srivastava, D. Pediatr. Res. (2006) [Pubmed]
  3. Altered whisker patterns induced by ectopic expression of Shh are topographically represented by barrels. Ohsaki, K., Osumi, N., Nakamura, S. Brain Res. Dev. Brain Res. (2002) [Pubmed]
  4. Altered neural cell fates and medulloblastoma in mouse patched mutants. Goodrich, L.V., Milenković, L., Higgins, K.M., Scott, M.P. Science (1997) [Pubmed]
  5. 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]
  6. Primary cilia regulate Shh activity in the control of molar tooth number. Ohazama, A., Haycraft, C.J., Seppala, M., Blackburn, J., Ghafoor, S., Cobourne, M., Martinelli, D.C., Fan, C.M., Peterkova, R., Lesot, H., Yoder, B.K., Sharpe, P.T. Development (2009) [Pubmed]
  7. Dynamic changes in the response of cells to positive hedgehog signaling during mouse limb patterning. Ahn, S., Joyner, A.L. Cell (2004) [Pubmed]
  8. Evidence for an expansion-based temporal Shh gradient in specifying vertebrate digit identities. Harfe, B.D., Scherz, P.J., Nissim, S., Tian, H., McMahon, A.P., Tabin, C.J. Cell (2004) [Pubmed]
  9. Hedgehog-mediated patterning of the mammalian embryo requires transporter-like function of dispatched. Ma, Y., Erkner, A., Gong, R., Yao, S., Taipale, J., Basler, K., Beachy, P.A. Cell (2002) [Pubmed]
  10. 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]
  11. Role of Sonic hedgehog in the development of the trachea and oesophagus. Ioannides, A.S., Henderson, D.J., Spitz, L., Copp, A.J. J. Pediatr. Surg. (2003) [Pubmed]
  12. Specification of the mammalian cochlea is dependent on Sonic hedgehog. Riccomagno, M.M., Martinu, L., Mulheisen, M., Wu, D.K., Epstein, D.J. Genes Dev. (2002) [Pubmed]
  13. An inversion involving the mouse Shh locus results in brachydactyly through dysregulation of Shh expression. Niedermaier, M., Schwabe, G.C., Fees, S., Helmrich, A., Brieske, N., Seemann, P., Hecht, J., Seitz, V., Stricker, S., Leschik, G., Schrock, E., Selby, P.B., Mundlos, S. J. Clin. Invest. (2005) [Pubmed]
  14. Shh signaling within the dental epithelium is necessary for cell proliferation, growth and polarization. Gritli-Linde, A., Bei, M., Maas, R., Zhang, X.M., Linde, A., McMahon, A.P. Development (2002) [Pubmed]
  15. Interplays of Gli2 and Gli3 and their requirement in mediating Shh-dependent sclerotome induction. Buttitta, L., Mo, R., Hui, C.C., Fan, C.M. Development (2003) [Pubmed]
  16. Interaction between the signaling molecules WNT7a and SHH during vertebrate limb development: dorsal signals regulate anteroposterior patterning. Yang, Y., Niswander, L. Cell (1995) [Pubmed]
  17. A positive feedback loop coordinates growth and patterning in the vertebrate limb. Niswander, L., Jeffrey, S., Martin, G.R., Tickle, C. Nature (1994) [Pubmed]
  18. A duplicated zone of polarizing activity in polydactylous mouse mutants. Masuya, H., Sagai, T., Wakana, S., Moriwaki, K., Shiroishi, T. Genes Dev. (1995) [Pubmed]
  19. Dorsal-ventral patterning of the spinal cord requires Gli3 transcriptional repressor activity. Persson, M., Stamataki, D., te Welscher, P., Andersson, E., Böse, J., Rüther, U., Ericson, J., Briscoe, J. Genes Dev. (2002) [Pubmed]
  20. Purkinje-cell-derived Sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum. Wallace, V.A. Curr. Biol. (1999) [Pubmed]
  21. Sonic hedgehog activates mesenchymal Gli1 expression during prostate ductal bud formation. Lamm, M.L., Catbagan, W.S., Laciak, R.J., Barnett, D.H., Hebner, C.M., Gaffield, W., Walterhouse, D., Iannaccone, P., Bushman, W. Dev. Biol. (2002) [Pubmed]
  22. Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus. Motoyama, J., Liu, J., Mo, R., Ding, Q., Post, M., Hui, C.C. Nat. Genet. (1998) [Pubmed]
  23. Inducible production of interferon-gamma in the developing brain causes cerebellar dysplasia with activation of the Sonic hedgehog pathway. Wang, J., Lin, W., Popko, B., Campbell, I.L. Mol. Cell. Neurosci. (2004) [Pubmed]
  24. Hoxd-12 differentially affects preaxial and postaxial chondrogenic branches in the limb and regulates Sonic hedgehog in a positive feedback loop. Knezevic, V., De Santo, R., Schughart, K., Huffstadt, U., Chiang, C., Mahon, K.A., Mackem, S. Development (1997) [Pubmed]
  25. Myf5 is a direct target of long-range Shh signaling and Gli regulation for muscle specification. Gustafsson, M.K., Pan, H., Pinney, D.F., Liu, Y., Lewandowski, A., Epstein, D.J., Emerson, C.P. Genes Dev. (2002) [Pubmed]
  26. Distinct regulators of Shh transcription in the floor plate and notochord indicate separate origins for these tissues in the mouse node. Jeong, Y., Epstein, D.J. Development (2003) [Pubmed]
  27. Beta1-integrins are critical for cerebellar granule cell precursor proliferation. Blaess, S., Graus-Porta, D., Belvindrah, R., Radakovits, R., Pons, S., Littlewood-Evans, A., Senften, M., Guo, H., Li, Y., Miner, J.H., Reichardt, L.F., Müller, U. J. Neurosci. (2004) [Pubmed]
  28. Inhibition of sonic hedgehog autoprocessing in cultured mammalian cells by sterol deprivation. Guy, R.K. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  29. Embryonic expression of cholesterogenic genes is restricted to distinct domains and colocalizes with apoptotic regions in mice. Laubner, D., Breitling, R., Adamski, J. Brain Res. Mol. Brain Res. (2003) [Pubmed]
  30. FGF4, a direct target of LEF1 and Wnt signaling, can rescue the arrest of tooth organogenesis in Lef1(-/-) mice. Kratochwil, K., Galceran, J., Tontsch, S., Roth, W., Grosschedl, R. Genes Dev. (2002) [Pubmed]
  31. 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]
  32. Sonic hedgehog signaling regulates Gli3 processing, mesenchymal proliferation, and differentiation during mouse lung organogenesis. Li, Y., Zhang, H., Choi, S.C., Litingtung, Y., Chiang, C. Dev. Biol. (2004) [Pubmed]
  33. Wnt5a regulates Shh and Fgf10 signaling during lung development. Li, C., Hu, L., Xiao, J., Chen, H., Li, J.T., Bellusci, S., Delanghe, S., Minoo, P. Dev. Biol. (2005) [Pubmed]
  34. Wnt signaling interacts with Shh to regulate taste papilla development. Iwatsuki, K., Liu, H.X., Grónder, A., Singer, M.A., Lane, T.F., Grosschedl, R., Mistretta, C.M., Margolskee, R.F. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  35. The Hedgehog-binding proteins Gas1 and Cdo cooperate to positively regulate Shh signaling during mouse development. Allen, B.L., Tenzen, T., McMahon, A.P. Genes Dev. (2007) [Pubmed]
  36. Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours. Dahmane, N., Lee, J., Robins, P., Heller, P., Ruiz i Altaba, A. Nature (1997) [Pubmed]
  37. The Sonic Hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis. Dahmane, N., Sánchez, P., Gitton, Y., Palma, V., Sun, T., Beyna, M., Weiner, H., Ruiz i Altaba, A. Development (2001) [Pubmed]
  38. Regulation of Tbx3 expression by anteroposterior signalling in vertebrate limb development. Tümpel, S., Sanz-Ezquerro, J.J., Isaac, A., Eblaghie, M.C., Dobson, J., Tickle, C. Dev. Biol. (2002) [Pubmed]
  39. Sonic hedgehog expression and role in healing corneal epithelium. Saika, S., Muragaki, Y., Okada, Y., Miyamoto, T., Ohnishi, Y., Ooshima, A., Kao, W.W. Invest. Ophthalmol. Vis. Sci. (2004) [Pubmed]
  40. Gli3 null mice display glandular overgrowth of the developing stomach. Kim, J.H., Huang, Z., Mo, R. Dev. Dyn. (2005) [Pubmed]
  41. Sonic hedgehog signaling plays an essential role during embryonic salivary gland epithelial branching morphogenesis. Jaskoll, T., Leo, T., Witcher, D., Ormestad, M., Astorga, J., Bringas, P., Carlsson, P., Melnick, M. Dev. Dyn. (2004) [Pubmed]
 
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