Disease relevance of hh

• Wingless and Hedgehog pattern Drosophila denticle belts by regulating the production of short-range signals [1].
• In addition, we found that edema factor, a potent adenylate cyclase, inhibits the hh pathway during wing development, consistent with the known role of cAMP-dependent PKA in suppressing the Hedgehog response [2].
• Recent work has established that activation of Hedgehog/patched signalling plays a key role in the development of basal cell carcinomas (BCCs) [3].
• During development of the Drosophila visual center, photoreceptor cells extend their axons (R axons) to the lamina ganglion layer, and trigger proliferation and differentiation of synaptic partners (lamina neurons) by delivering the inductive signal Hedgehog (Hh) [4].
• More recently, we have demonstrated the importance of Hedgehog signaling in humans for advanced prostate cancer [5].

High impact information on hh

• Ciliogenesis defects in embryos lacking inturned or fuzzy function are associated with failure of planar cell polarity and Hedgehog signaling [6].
• The secreted signaling molecule Hedgehog regulates gene expression in target cells in part by preventing proteolysis of the full-length Cubitus interruptus (Ci-155) transcriptional activator to the Ci-75 repressor form [7].
• Further, we demonstrate an absolute requirement for Hedgehog signaling in sclerotomal development and a role in cardiac morphogenesis [8].
• Misexpression of hh in the soma induces germ cells to migrate to inappropriate locations [9].
• Opposing transcriptional outputs of Hedgehog signaling and engrailed control compartmental cell sorting at the Drosophila A/P boundary [10].

Biological context of hh

• Direct Wg autoregulation (autocrine signalling) is masked by its paracrine role in maintaining hh, which in turn maintains wg [11].
• Expression of CI(m1-4), but not CI(wt), can rescue the hh mutant phenotype and restore wg expression in hh mutant embryos [12].
• Moreover, while the effects of Hh are primarily concentration dependent in other tissues, hh signaling in the eye acts as a binary switch to initiate retinal morphogenesis by inducing expression of the tissue-specific factor Eya [13].
• The ratio of these forms, which is regulated positively by hh signaling and negatively by PKA activity, determines the on/off status of hh target gene expression [12].
• This report examines the role during early oogenesis of several genes that are known to function in hh-mediated signaling during embryonic and larval development (P. Ingham (1995) Current Opin. Genetics Dev. 5, 528-534) [14].

Anatomical context of hh

• Loss of hh function (while maintaining wg activity) results in the absence of the Eve cells, whereas the Lbe cells are expanded within the cardiac mesoderm [15].
• In this report, we demonstrate that the retinal determination gene eyes absent (eya) is the crucial link between the Hedgehog signaling pathway and photoreceptor differentiation [13].
• During Drosophila wing development, Hedgehog (Hh) signalling is required to pattern the imaginal disc epithelium along the anterior-posterior (AP) axis [16].
• We show that the transcription of seven up (svp), which is expressed in the two most posterior pairs of cardioblasts in each segment, is dependent on hedgehog (hh) signaling from the dorsal ectoderm [17].
• These studies suggest the conservation of the hh signaling pathway in controlling epithelial stem cell divisions among different organisms [18].

Associations of hh with chemical compounds

• Abrogation of heparan sulfate synthesis in Drosophila disrupts the Wingless, Hedgehog and Decapentaplegic signaling pathways [19].
• Cholesterol plays a critical role in Hedgehog (Hh) signaling by facilitating the regulated secretion and sequestration of the Hh protein [16] [corrected], to which it is covalently coupled [20].
• The Drosophila segment polarity gene fused encodes a putative protein-serine/threonine kinase, and plays a critical role in the signal transduction for Hedgehog (Hh)-dependent gene expression [21].
• The Wingless and Hedgehog organizing activities help to establish two more stripes per segment that localize ligands for the Epidermal Growth Factor and the Notch signalling pathways, respectively [22].
• These data suggest that the importance of the N-terminal cysteine of mature Hedgehog in patterning appendages differs between species [23].

Physical interactions of hh

• It is not known how the Hedgehog signal is relayed from Smoothened to the regulatory complex nor how responses to different levels of Hedgehog are implemented [24].
• In Drosophila, Hedgehog signaling regulates transcription of target genes by modifying the activity of the DNA-binding protein Cubitus interruptus (Ci) [25].
• Reading the Hedgehog morphogen gradient by measuring the ratio of bound to unbound Patched protein [26].

Enzymatic interactions of hh

• Here we demonstrate that the PKA pathway antagonizes the hh pathway by phosphorylating CI [27].

Regulatory relationships of hh

• Shaggy/GSK3 antagonizes Hedgehog signalling by regulating Cubitus interruptus [28].
• In early larval development, a short-range Hedgehog signal originating from the posterior compartment of the imaginal wing disc activates expression of genes including decapentaplegic (dpp) in a stripe running along the anterior-posterior compartment boundary [29].
• In this article, we show that hh is maintained in a repressed state by the Polycomb group (PcG) chromatin proteins [30].
• Altered localization of Drosophila Smoothened protein activates Hedgehog signal transduction [31].
• Activation of Hedgehog signaling generates a long-range signal which can promote macrochaete formation in the Wingless activity domain [32].

Other interactions of hh

• Costal2, a novel kinesin-related protein in the Hedgehog signaling pathway [33].
• Here we show that Sgg is also a negative regulator in the Hedgehog (Hh) pathway [28].
• Posterior cells continuously express and require engrailed (en) and secrete Hedgehog (Hh) protein [34].
• Combgap participates in a Hedgehog-controlled circuit in the developing wing and leg by regulating the expression of Cubitus interruptus [35].
• Nor does the ectopic expression of wg or dpp mimic the effect of ectopic hh expression [14].

Analytical, diagnostic and therapeutic context of hh

• Patched (Ptc), the receptor for the morphogen Hedgehog (Hh), is active in the absence of ligand and blocks the expression of target genes by inhibiting Smoothened (Smo), an essential transducer of the Hh signal [26].
• Sequence analysis reveals a motif characteristic of a transmembrane domain, suggesting that the hh protein is membrane-associated. hh expression in epidermal cells is confined to the posterior compartments and coincides precisely with that of engrailed (en) [36].
• Residues in the Hh-C17 active site have been identified, and their role in Hedgehog autoprocessing probed by site-directed mutagenesis [37].
• Using low stringency hybridization and degenerate PCR primers, we have isolated complete or partial hh-like sequences from a range of invertebrate species including other insects, leech and sea urchin [38].
• N-terminal recombinant Sonic Hedgehog protein (SHH-N) was added to rat retinal cultures for 3-12 d, and the numbers of retinal cells of various phenotypes were analyzed by immunohistochemistry [39].

References