l(3)neo56, bar-3, Mrt
Hedgehog N-terminal signaling domain and C-terminal autoprocessing domain - helps establish embryonic segmentation - a segment polarity intercellular signaling protein - cooperates with Frazzled to guide axons through a non-canonical signalling pathway - A local difference in Hedgehog signal transduction increases mechanical cell bond tension and biases cell intercalations along the Drosophila anteroposterior compartment boundary
Gene model reviewed during 5.44
Gene model reviewed during 5.48
There is only one protein coding transcript and one polypeptide associated with this gene
Interacts with shf.
The C-terminal domain displays autoproteolytic activity. Cleavage of the full-length hedgehog protein is followed by the covalent attachment of a cholesterol moiety to the C-terminus of the newly generated N-terminal fragment (N-product).
Cholesterol attachment plays an essential role in restricting the spatial distribution of hedgehog activity to the cell surface.
N-terminal palmitoylation of the hedgehog N-product is required for the embryonic and larval patterning activities of the hedgehog signal. Rasp acts within the secretory pathway to catalyze the N-terminal palmitoylation of Hh.
Click to get a list of regulatory features (enhancers, TFBS, etc.) and gene disruptions (point mutations, indels, etc.) within or overlapping Dmel\hh using the Feature Mapper tool.
hh RNA can be detected in ganglion mother cells at 72 hours after larval hatching (ALH), but not at 48 hours ALH.
hh is expressed strongly in the anterior escort cells, and weakly in the posterior escort cells
At early stage 11, hh expression extends from the posterior optic lobe into the anterior optic lobe. It becomes restricted to the posterior optic lobe at mid stage 11 and later localizes to Bolwig organ precursor cells in the ventral posterior optic lobe. hh is expressed in cells immediately anterior to the tracheal pits.
hh transcripts are expressed in embryos, larvae, pupae and adults with peaks of expression in 6-12hr embryos and early pupae. Transcripts are first detected in embryonic stage 5 in a few stripes at the anterior and posterior ends of the embryo. The number of stripes gradually increases to 17. The terminal stripes are 2-3 cells wide and the internal stripes are 1 cell wide. Expression is stronger in every second stripe and is stronger laterally than in dorsal and ventral regions. The expression in stripes reaches a maximum at stages 8-11. By the end of germband retraction, the stripes are situated in the posterior compartments of the lateral ectoderm.
Peaks of hh expression are observedin 2-10hr embryos and in pupae. In embryos, hh transcripts are firstexpressed in a discrete pattern in the maxillary segment followed by apattern of 14 parasegmental stripes. At germ band extension, a 15th stripeis seen. hh expression in the metameric portion of the embryo closelyresembles en expression. Expression is also described in a variety ofsites in the nonmetameric portion of the embryo including the intercalaryand antennal segments, the procephalon, the gnathal segments, and portionsof the hindgut. Expression in imaginal discs is described for theassociated Ecol\lacZ insertion. hh expression is pair-rule dependent. Inftz mutants, expression in the even-numbered parasegments is missing.wg mutations caused diminished expression and ptc mutants causeexpression in an ectopic stripe in each segment. nkd mutations causebroadening of the stripes.
hh transcripts are first detected at the cellular blastoderm stage in 17 segmental stripes. 14 of the stripes are one cell wide and extend from 10-70% egg length. There are two 3-cell-wide stripes at 5% and 75% egg length and a dorsal anterior spot at 97% egg length. The stripes appear asynchronously. Even parasegmentally-numbered stripes precede odd-numbered stripes and anterior stripes precede more posterior stripes. The stripes are activated around the entire circumference of the embryo but disappear from the amnioserosa and mesoderm after gastrulation. At stage 11, the stripes are located just posterior to the parasegmental furrow and are spaced one cell anterior to the tracheal pit in each segment. Stripes persist after germ band retraction and are located in the posteriormost portion of the lateral ectoderm of each segment. hh transcripts are also expressed in the fore- and hindguts following gastrulation and germ band extension as well as in the cephalic region of the embryo. Up to stage 10, the intensity of staining is heavier in the nucleus than in the cytoplasm. After stage 10, RNA staining is predominantly cytoplasmic.
At the cellular blastoderm stage, hh transcripts are located predominantly in a single stripe at 75% egg length with additional transcripts at the anterior tip and along the ventral side. At gastrulation, hh is expressed in 14 single-cell-wide stripes between 30% and 65% egg length. The stripes are coincident with en expression and occur in the cells of the posterior compartments. They appear in a characteristic order, even-numbered ones before odd-numbered ones and anterior ones before posterior ones. hh is also expressed in a block of cells at the anterior end and in wide stripes at 10% and 75% egg length. hh transcripts are expressed later in the foregut, pharynx, esophagus, hindgut, and salivary glands. hh transcripts are exressed in imaginal discs where they are localized to the posterior compartments. The differences between hh and en expression are noted.
GBrowse - Visual display of RNA-Seq signalsView Dmel\hh in GBrowse 2
Please Note This section lists cDNAs and ESTs that fall within the genomic extent of the gene model, which may include cDNAs and ESTs of genes within introns, or of overlapping genes. Please see GBrowse for alignment of the cDNAs and ESTs to the gene model.
For each fully sequenced cDNA the DGRC maintains various forms of the cDNA (e.g tagged or untagged) in several different host vectors for subsequent cloning and expression in Drosophila and Drosophila cell lines.
One of 42 Drosophila genes identified as being most likely to reveal molecular and cellular mechanisms of nervous system development or plasticity relevant to human Mental Retardation disorders.
Cholesterol modification of hh protein is necessary (in the embryonic epidermis) for its assembly in large punctate subcellular structures and apical sorting through the activity of the disp protein. Movement of these specialized structures containing hh protein through the cellular field is contingent upon the activity of ttv.
The expression of hh in the wing disc, once activated, is dependent on ph-p, trx and brm. This may be due to an element upstream of the hh transcriptional start site (hh-CMM) that can bind Pc protein and is able to act as a cellular memory module (CMM) when placed upstream of a UAS sequence in reporter constructs.
Misexpression of hh in the soma induces germ cells to migrate to inappropriate locations in the developing embryo.
hh may act as an attractive guidance cue in germ cell migration in the embryo.
Migration of all tracheal branches is absent or stalled in hh-mutant embryos.
hh signalling from the peripodial membrane, but not from the disc proper, is required for eye disc patterning and growth.
hh is required in the developing eye both for the induction of ato expression that prefigures the position of the R8 cells, and for the repression of ato expression between the nascent proneural clusters. Both effects are due to the direct stimulation of responding cells by the hh gene product itself.
In the absence of hh activity, prothoracic leg disc fragments fail to undergo anterior/posterior conversion, but can still regenerate missing anterior pattern elements. hh-independent regeneration (integration) may be mediated by the wg and dpp positional cues.
Three EMS induced alleles were identified in a screen for mutations affecting commissure formation in the CNS of the embryo.
hh signalling, coming from the adjacent P compartments across both Anterior/Posterior and Posterior/Anterior boundaries in the abdomen, organizes the pattern of all the Anterior cells.
hh plays a role in the formation of the posterior barrier to wg movement at the presumptive embryonic segment border. Increased hh signalling decreases the domain of wg action in the anterior direction.
fu is required autonomously in anterior cells neighboring hh to maintain ptc and wg expression. wg is in turn maintaining en and hh expression. The hh signalling components smo and ci are required in cells posterior to hh to maintain ptc expression, whereas fu is not necessary in these cells.
ptc protein normally binds hh gene product without any help of the smo gene product, though smo is also a part of the receptor complex that binds hh and transduces the hh signal. The mechanism of signal transduction may involve hh binding specifically to ptc and inducing a conformational change leading to the release of latent smo activity.
hh and spi bring about the concerted assembly of ommatidial and synaptic cartridge units, imposing the "neurocrystalline" order of the compound eye onto the post-synaptic target field. hh encodes an inductive signal that is transported along retinal axons from the developing eye, and induces the expression of Egfr in post-synaptic precursor cells.
In the absence of hh signalling results propose that Su(fu) inhibits ci by binding to it and that, upon reception of the hh signal, fu is activated and counteracts Su(fu), leading to the activation of ci.
Mutants are isolated in an EMS mutagenesis screen to identify zygotic mutations affecting germ cell migration at discrete points during embryogenesis: mutants exhibit segment polarity pattern defects.
Each primordia of the genital disc (female genital, male genital and anal primordia) is divided into anterior and posterior compartments. Clonal phenotype of genes known to play compartment specific functions demonstrate the anterior/posterior patterning functions of these genes are conserved in the genital disc.
Genetic combinations with mutants of nub cause additive phenotypes.
Clonal analysis demonstrates hh has two distinct functions: expression is required in the photoreceptor cells to drive the morphogenetic furrow and in addition hh secreted from cells at the posterior disc margin is absolutely required for the initiation of patterning and predisposes ommatidial precursor cells to enter ommatidial assembly later.
hh induces ommatidial development in the absence of its secondary signals wg and dpp. Regulatory relationships between hh, dpp and wg in the eye are similar to those found in other imaginal discs, such as the leg.
hh protein secreted by posterior compartment cells plays a key role in patterning the posterior portion of the anterior compartment in adult abdominal segments.
dpp specifies the position of most of the sensory organ precursors (SOPs) in the notum and some of them in the wing. Close to the A/P compartment border of the wing, however, SOPs are specified by hh rather than by dpp alone.
hh elicits signal transduction via a complex that includes the products of the fu, ci and cos genes. The complex binds with high affinity to microtubules in the absence of hh protein, but not when hh is present. The complex may facilitate signalling from hh by governing access of the ci product to the nucleus.
The affinity boundary that segregates A and P cells into adjacent but immiscible cell populations is to a large extent a consequence of local hh signalling, rather than a reflection of an intrinsic affinity difference between A and P cells.
Comparing the biological activities of secreted and membrane-tethered hh protein provides evidence that hh forms a local concentration gradient and functions as a concentration-dependent morphogen in the wing.
The pattern of expression of hh in the larval and adult abdomen has been analysed.
The function of hh in morphogenetic furrow progression is indirect. Cells that cannot receive/transduce the hh signal (as in smo clones) are still capable of entering a furrow fate and differentiating normally. However hh is required to promote furrow progression and regulate its rate of movement across the disc, since the furrow is delayed in smo clones.
Elevated levels of ci are sufficient to activate hh target genes, even in the absence of hh activity. ci activates transcription in yeast by a GLI consensus-binding site and the zinc finger domain is sufficient for its target specificity. Results strongly support a role for ci as the transcriptional activator that mediates hh signaling.
hh is required for the normal activation of bap and srp in anterior portions of each parasegment, whereas wg is required to suppress bap and srp expression in posterior portions. hh and wg play opposing roles in mesoderm segmentation.
wg and hh signaling account for all cell types across the dorsal epidermis. dpp does not appear to mediate this hh dorsal epidermis signaling. hh antagonizes the activity of ptc in the specification of primary and secondary but not tertiary cell types. hh also antagonizes lin function.
Distinction between dorsal and ventral fates is maintained through mutual repression by dpp and wg. Expression of wg and dpp in their normal domains depends on the hh signal. Cells that are not likely to be within range of the wg or dpp signals have a different capacity to respond to hh.
smo activity is required in wing anterior cells along the A/P boundary for these cells both to transduce hh and to limit its further movement into the anterior compartment. ptc regulates smo activity in response to hh signalling.
Cells in anterior compartments lacking ci express hh and adopt a posterior fate without expressing en. Increased levels of ci can induce the expression of dpp independent of hh. Expression of ci in anterior cells controls limb development by restricting hh secretion to posterior cells and by conferring competence to respond to hh by mediating transduction of the hh signal.
ptc and ci are expressed in a pattern complementary to hh and en in adult ovaries. Ectopic expression of hh results in the ectopic expression of ptc. hh directly effects region 2 somatic cells of the germarium via a signalling pathway which includes ptc and ci, but not wg or dpp.
hh is required for the proliferation and specification of ovarian somatic cells prior to egg chamber formation. hh signalling during egg chamber assembly appears to be closley related to, or part of pathways involving the neurogenic genes.
The expression pattern of a number of genes in the larval genital discs, including a hh-Ecol\lacZ reporter gene, has been studied to determine the segment-parasegment organisation of the genital discs.
ara-caup expression at patches on the wing, located one at each side of the DV compartment border, is mediated by the hh signal through its induction of high levels of ci protein in anterior cells near to the AP compartment border.
hh, wg and dpp are required for the establishment of signaling centres that coordinate morphogenesis in the hindgut epithelium. Activation of these genes in the developing hindgut and foregut requires fkh. hh and wg activities in the gut epithelial cells are required for the expression of the homeobox gene bap in the ensheathing visceral mesoderm.
The secreted hh product regulates the temporal assembly of photoreceptor precursor cells into ommatidia in the eye and is transmitted along the retinal axons to serve as the inductive signal in the brain, triggering neurogenesis in the developing visual centers. hh acts in the first of two retinal axon-mediated steps in the assembly of lamina synaptic cartridges.
The hh autoprocessing reaction proceeds via an internal thioester intermediate and results in a covalent modification that increases the hydrophobic character of the signalling domain and influences its spatial and subcellular distribution. Truncated, unprocessed amino terminal protein causes embryonic mispatterning, suggesting a role for autoprocessing in spatial regulation of hh signalling.
Cholesterol is the lipophilic moiety covalently attached to the amino-terminal signalling domain during autoprocessing. The carboxy-terminal domain acts as an intramolecular cholesterol transferase.
hh and wg specify the identities of specific regions of the head capsule. During eye-antennal disc development hh and wg expression initially overlap, but subsequently segregate. This regional segregation is critical to head specification and is regulated by oc. oc is a candidate hh target gene during early eye-antennal disc development.
In competition binding, cross-linking and co-immunoprecipitation experiments no binding of tagged hh protein to smo protein or its rat homolog could be detected, although hh protein can bind to the protein encoded by the mouse homolog of ptc.
fu protein is phosphorylated during embryogenesis as a result of hh activity. Results from cell culture studies suggest that fu and Pka-C1 function downstream of hh but in parallel pathways that eventually converge distal to fu.
Segment polarity gene smo is required for the response of cells to hh signalling during the development of both the embryonic segments and imaginal discs. Structure of the smo protein suggests it may act as a receptor for the hh ligand.
hh protein acts in the wing as a signal to instruct neighbouring cells to adopt fates appropriate to the region of the wing just anterior to the compartmental boundary. Some members of the trx group genes are involved in the transcriptional regulation of genes in the hh signalling pathway during imaginal development, Pc group genes are not involved in this regulation pathway.
Ectopic expression of the amino-terminal half of the hh protein results in effects similar to those induced by the wild-type protein, altering the identity of cells of both the dorsal and ventral ectoderm of the developing embryo and of cells of the anterior compartment of the imaginal discs. Ectopic expression of a form of the protein in which the signal cleavage sequence is mutated has no effect on larval or adult development. Results suggest that all signaling activity of the hh protein is most likely to reside in the amino terminal fragment generated by autoproteolysis.
Ectopic expression of hh produces ectopic furrows in the anterior eye disc. In addition to changes in cell shape the ectopic furrows are associated cell proliferation, cell cycle synchronisation and pattern formation, events that parallel normal furrow progression. Results propose that the morphogenetic furrow coincides with a transient boundary that coordinates growth and differentiation of the eye disc and hh is necessary and sufficient to propagate this boundary across the epithelium.
Pka-C1 is essential during limb development to prevent inappropriate dpp and wg expression. A constitutively active form of Mmus\Pkaca, can prevent inappropriate dpp and wg expression but does not interfere with their normal induction by hh. The basal activity of Pka-C1 imposes a block on the transcription of dpp and wg and hh exerts its organizing influence by alleviating the block.
hh, wg and mys are required for epithelial morphogenesis during proventriculus organ development. The morphogenetic process is suppressed by dpp. These results identify a novel cell signalling centre in the foregut that operates through a distinct genetic circuitry in the midgut to direct the formation of a multiply folded organ from a simple epithelial tube.
hh pathway mutants induce ectopic morphogenetic furrows. Results show that ommatidial clusters are self-organising units whose polarity in one axis is determined by the direction of furrow progression and which can independently define the position of an equator without reference to the global coordinates of the eye disc.
en governs growth and patterning in both anterior and posterior wing compartments by controlling the expression of the hh and dpp products as well as the response of the cells to them. en activity programs wing cells to express hh whereas the absence of en activity programs them to respond to hh by expressing dpp. Consequently, posterior cells secrete hh product and induce a stripe of neighboring anterior cells across the compartment boundary to secrete dpp. dpp may exert its organizing influence by acting as a gradient morphogen in contrast to hh which appears to act principally as a short range inducer of dpp.
Ectopic expression of hh can induce ectopic wg and dpp expression in anterior cells and reorganise the anterior compartment pattern. Loss of endogenous hh blocks wg and dpp expression along the compartment boundary and impedes growth and patterning in both compartments.
Ectopic expression of hh in the anterior compartment of the wing disc causes overgrowth and pattern duplications in both anterior and posterior compartments of the wing disc, similar to alterations seen with ectopic dpp expression. These results indicate that hh is acting as a regulator of dpp expression and dpp acts as an organising molecule controlling growth and patterning in the wing imaginal disc.
Direct wg autoregulation differs from wg signalling to adjacent cells in the importance of fu, smo and ci relative to sgg and arm. Early wg autoregulation during the hh-dependent stage differs from later wg autoregulation.
Comparisons of early development to that in other insects have revealed conservation of some aspects of development, as well as differences that may explain variations in early patterning events.
hh gene product is involved in regulating ptc expression in both embryo and discs, through its role in regulating gene expression along the anterior-posterior compartment border. hh function establishes the proximodistal axis in discs. hh protein is secreted and can cross embryo parasegment borders and the anterior-posterior compartment border of imaginal discs to neighbouring cells that express neither en nor hh. In the embryo hh regulation of ptc apparently facilitates ptc and wg expression. In the discs hh regulation of ptc and other genes in the anterior compartment helps to establish the proximodistal axis. Cell-cell communication mediated by hh links the special properties of compartment borders with specification of the proximodistal axis in imaginal development.
Wild type activity of five segment polarity genes, wg, ptc, en, nkd and hh, can account for most of the ventral pattern elements in the embryo. wg is required for naked cuticle and en is required for the first row of denticles in each abdominal denticle belt. Remaining cell types are produced by different combinations of the five gene activities. wg generates the diversity of cell types within the segment but each specific cell identity depends on the activity of ptc, en, nkd and hh. hh and en contribute to the pattern independently. hh and ptc show mutual suppression through opposing effects on wg expression. hh alters the competence of cells to respond to wg signal.
Developing retinal cells drive the progression of morphogenesis using the products of the hh and dpp genes. Clonal analysis suggests that gene products act as diffusible signals. hh induces the expression of dpp, the primary mediator of furrow movement.
Segment polarity mutations cause stripes of abnormal patterning within sectors of the leg disc, which may be mediated by regional perturbations in growth.
The ptc and hh genes encode components of a signal transduction pathway that regulate the expression of wg transcription following its activation by pair rule genes, but most other aspects of wg expression are independent of ptc and hh. Maintenance of wg expression depends upon the activity of hh, which acts only on neighboring cells to maintain wg expression. Expression of wg in the absence of ptc depends on hh.
Competence of cells to express wg is independent of their ability to receive the hh signal. wg activation requires the function of fu, this suggests that the putative hh signal is transduced by the serine/threonine kinase that fu encodes.
A hh-related gene family has been identified in the zebrafish. Over-expression of one member, sonic hedgehog, in fly embryos, can activate the hh-dependent pathway.
Many alleles of hh act as dominant alleles of gl.
hh expression posterior to the morphogenetic furrow in the developing eye disc is continuously required for its progression. The forward diffusion of hh protein induces anterior cells to enter the furrow. hh acts upstream of gl, sca, h and dpp in the developing eye.
Although hh is essential for wg function in segmentation, wg appears to be still capable of some action in hh's absence.
Probably encodes a secreted or transmembrane protein.
The pattern of hh protein expression during embryonic development has been analysed.
hh gene cloned by plasmid rescue, the encoded protein is targetted to the secretory pathway (consistant with the non-cell autonomous requirement for hedgehog in cuticular patterning) and is expressed coincidentally with engrailed in embryos and imaginal discs. Maintainance of hh expression is dependent upon other segment polarity genes including engrailed and wingless. The amino acid sequence shows no similarity to any known protein but hydropathy analysis highlights a prominent hydrophobic region.
Sequence analysis of hh indicates that the gene product contains a putative transmembrane domain which suggests that it may be localized at the cell surface and be involved in cell-cell communication.
hh gene cloned and the sequence suggests a membrane associated protein. Expression pattern analysed and found to coincide with that of en in the epidermis. Though initially independent of en, hh expression later becomes en-dependent.
hh cannot completely rescue the ptc phenotype when in double mutant combinations.
The role of ptc in positional signalling is permissive rather than instructive, its activity is required to suppress wg transcription in cells predisposed to express wg. These cells receive an extrinsic signal, encoded by hh, that antagonises the repressive activity of ptc. Results suggest that ptc protein may be the receptor for the hh signal, implying that this is an usual mechanism of ligand-dependent receptor inactivation.
hh is essential for maintaining the normal pattern of ptc expression.
Role of hh in neurogenesis has been studied.
Adult eyes are small, narrow with about 150 facets, eye disc is small due to precursor cell defects.
The mutational effects of hh on larval and adult cuticular patterns has been studied. Defects in the distal portions of the legs and antenna occur in association with homozygous hh clones in the posterior compartments of the structures.
Genetic mosaics were used to determine that hh is not autonomous at the level of the single cell.
A segment polarity type of embryonic lethal. Homozygous embryos have the posterior naked portion of the ventral surface of each segment deleted and replaced by a mirror image of the anterior denticle belts. Embryos appear to lack segmental boundaries. In strong alleles, there is no obvious segmentation; the larvae are approximately 40% the length of the wild-type larvae and there is a lawn of denticles arranged in a number of whorls on the ventral surface as a result of loss of naked cuticle. In intermediate alleles, naked cuticle is also lost from the ventral region, but the lawn of denticles is arranged in segmental arrays in mirror-image symmetry. The weak alleles show fusions that delete the naked cuticle usually between abdominal segments 1 and 2 and 6, 7 and 8 (Mohler, 1988). Temperature shift experiments with a temperature-sensitive allele (viable and normal at 18oC, and mutant at 25oC) indicate two phases of hh activity at 25oC, the first during early embryogenesis (3-6 hr of development) and the second during the late larval and early pupal stages (4-7 days of development).