Disease relevance of Shh

• Abnormal activities of Shh signaling pathway have been implicated in tumorigenesis such as basal cell carcinomas and medulloblastomas [1].
• Targeted disruption of Shh in mouse leads to near complete absence of craniofacial skeletal elements at birth, and mutation of SHH in human causes holoprosencephaly (HPE), frequently associated with defects of derivatives of pharyngeal arches [2].
• We transfected an adenovirus harboring chicken Shh (Ad-cShh) to mouse embryos (E9.5-E11.5) using an in utero surgical technique [3].
• The PATCHED (PTC) gene encodes a Sonic hedgehog (Shh) receptor and a tumor suppressor protein that is defective in basal cell nevus syndrome (BCNS) [4].
• This study examined whether SHH, 2 other ligands IHH and Desert hedgehog, and receptors or downstream targets are expressed in normal gastric epithelium or in intestinal and diffuse-type gastric cancers [5].
• To further confirm that upregulation of Shh activity is responsible for the ectopic tooth formation, we analysed mice mutant for Gas1, a Shh protein antagonist in diastema mesenchyme [6].

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

• Wnt7a, which is expressed in dorsal ectoderm, provides the signal required for Shh expression and formation of posterior structures [16].
• Moreover, Shh expression in mesenchyme can be activated by FGF4 in combination with retinoic acid [17].
• In situ hybridization of the embryos of these mutants revealed ectopic expression of Shh and fibroblast growth factor-4 (Fgf-4) genes at the anterior margin of limb buds [18].
• This study identifies Sonic hedgehog (Shh) secreted by the notochord and/or floor plate as a primary regulator of auditory cell fates within the mouse inner ear [12].
• Sonic hedgehog (Shh) plays a critical role in organizing cell pattern in the developing spinal cord [19].

Associations of Shh with chemical compounds

• In organotypic cultures of developing rat prostates, Shh inhibited cell proliferation and promoted differentiation of luminal epithelial cells [1].
• Treatment of developing mice with hybridoma cells that secrete neutralizing anti-Shh antibodies [6] disrupted cerebellar development and reduced bromodeoxyuridine (BrdU) incorporation in the EGL of neonatal mice, whereas treatment of dissociated granule neuron cultures with recombinant Shh stimulated BrdU incorporation [20].
• This pattern of localized Shh expression occurs in response to testosterone stimulation [21].
• The secreted glycoprotein Sonic hedgehog (Shh) has been suggested to act as an endodermal signal that controls hindgut patterning and lung growth [22].
• Here we examined the role of interferon (IFN)-gamma in regulating the Sonic hedgehog (Shh) pathway and cerebellar development in bigenic mice with temporal control of IFN-gamma gene expression driven by a tetracycline-controllable promoter [23].

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

• Here we carried out tissue transplantations, grafted beads soaked in Shh, Bmps, and Noggin in chick limb buds, and analysed Tbx3 expression [38].
• Although exogenous Shh promotes epithelial cell proliferation in corneal organ culture, its expression in migrating epithelium in vivo does not counteract the suppression of cell proliferation at the early healing phase of epithelium debridement [39].
• CONCLUSIONS: Corneal epithelial debridement causes a transient upregulation of Shh expression and activation of Shh/Gli-3 signaling cascade in healing corneal and limbal epithelia [39].
• Although Gli2 principally mediates the activator function of Shh, surprisingly we observed minimal changes in glandular development in the Gli2 mutant stomach [40].
• Gene targeting studies indicate that sonic hedgehog (Shh) signaling plays an essential role during craniofacial development [41].

References