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PubMed2006

Hedgehog signaling in the normal and diseased pancreas.

The hedgehog (Hh) family of genes, sonic hedgehog (Shh), Indian hedgehog (Ihh), and desert hedgehog (Dhh) encode signaling molecules that regulate multiple functions during organ development and in adult tissues. Altered hedgehog signaling has been implicated in disturbed organ development as well as in different degenerative and neoplastic human diseases. Hedgehog signaling plays an important role in determination the fate of the mesoderm of the gut tube, as well as in early pancreatic development, and islet cell function. Recently, it has been shown that deregulation of hedgehog signaling molecules contributes to the pathogenesis and progression of pancreatic cancer and of chronic pancreatitis. Inhibition of hedgehog signaling using hedgehog antagonists reduces pancreatic cancer cell growth in vitro and in vivo, thus holding promise of novel agents in the treatment of this devastating disease. In this review, we discuss the role of hedgehog signaling during pancreatic development, its role in the pathogenesis of both chronic pancreatitis and pancreatic cancer, and lastly, the implications of this newly available information with regards to treatment of pancreatic cancer.

Animals↗
PubMed2003

Therapeutic efficacy of sonic hedgehog protein in experimental diabetic neuropathy.

Hedgehog proteins modulate development and patterning of the embryonic nervous system. As expression of desert hedgehog and the hedgehog receptor, patched-1, persist in the postnatal and adult peripheral nerves, the hedgehog pathway may have a role in maturation and maintenance of the peripheral nervous system in normal and disease states. We measured desert hedgehog expression in the peripheral nerve of maturing diabetic rats and found that diabetes caused a significant reduction in desert hedgehog mRNA. Treating diabetic rats with a sonic hedgehog-IgG fusion protein fully restored motor- and sensory-nerve conduction velocities and maintained the axonal caliber of large myelinated fibers. Diabetes-induced deficits in retrograde transport of nerve growth factor and sciatic-nerve levels of calcitonin gene-related product and neuropeptide Y were also ameliorated by treatment with the sonic hedgehog-IgG fusion protein, as was thermal hypoalgesia in the paw. These studies implicate disruption of normal hedgehog function in the etiology of diabetes-induced peripheral-nerve dysfunction and indicate that delivery of exogenous hedgehog proteins may have therapeutic potential for the treatment of diabetic neuropathy.

Animals↗
PubMed2001

Analysis of the zebrafish smoothened mutant reveals conserved and divergent functions of hedgehog activity.

Despite extensive studies, there are still many unanswered questions regarding the mechanism of hedgehog signaling and the phylogenic conservation of hedgehog function in vertebrates. For example, whether hedgehog signaling in vertebrates requires smoothened is unclear, and the role of hedgehog activity in zebrafish is controversial. We show that inactivation of smoothened by retroviral insertions in zebrafish results in defects that are characteristic of hedgehog deficiencies, including abnormalities in body size, the central nervous system, adaxial mesoderm, cartilage and pectoral fins. We demonstrate that, as in Drosophila, vertebrate smoothened is essential for hedgehog signaling, and functions upstream of protein kinase A. Further analysis of neural tube defects revealed the absence of lateral floor plate and secondary motoneurons, but the presence of medial floor plate and primary motoneurons in smoothened mutant embryos. Blocking maternal hedgehog signaling by cyclopamine eliminates primary motoneurons, but not medial floor plate. Interestingly, even after inhibition of maternal hedgehog activity, the midbrain dopaminergic neurons still form, and looping of the heart does not randomize in the mutants. We also found decreased proliferation and increased apoptosis in the mutants. Taken together, these data demonstrate the conserved role of vertebrate smoothened in the hedgehog signaling pathway, and reveal similarities and differences of hedgehog function between teleosts and amniotes.

Animals↗
PubMed2005

The you gene encodes an EGF-CUB protein essential for Hedgehog signaling in zebrafish.

Hedgehog signaling is required for many aspects of development in vertebrates and invertebrates. Misregulation of the Hedgehog pathway causes developmental abnormalities and has been implicated in certain types of cancer. Large-scale genetic screens in zebrafish have identified a group of mutations, termed you-class mutations, that share common defects in somite shape and in most cases disrupt Hedgehog signaling. These mutant embryos exhibit U-shaped somites characteristic of defects in slow muscle development. In addition, Hedgehog pathway mutations disrupt spinal cord patterning. We report the positional cloning of you, one of the original you-class mutations, and show that it is required for Hedgehog signaling in the development of slow muscle and in the specification of ventral fates in the spinal cord. The you gene encodes a novel protein with conserved EGF and CUB domains and a secretory pathway signal sequence. Epistasis experiments support an extracellular role for You upstream of the Hedgehog response mechanism. Analysis of chimeras indicates that you mutant cells can appropriately respond to Hedgehog signaling in a wild-type environment. Additional chimera analysis indicates that wild-type you gene function is not required in axial Hedgehog-producing cells, suggesting that You is essential for transport or stability of Hedgehog signals in the extracellular environment. Our positional cloning and functional studies demonstrate that You is a novel extracellular component of the Hedgehog pathway in vertebrates.

Animals↗
PubMed1997

Sonic hedgehog promotes rod photoreceptor differentiation in mammalian retinal cells in vitro.

The hedgehog gene family encodes secreted proteins important in many developmental patterning events in both vertebrates and invertebrates. In the Drosophila eye disk, hedgehog controls the progression of photoreceptor differentiation in the morphogenetic furrow. To investigate whether hedgehog proteins are also involved in the development of the vertebrate retina at stages of photoreceptor differentiation, we analyzed expression of the three known vertebrate hedgehog genes. We found that Sonic hedgehog and Desert hedgehog are expressed in the developing retina, albeit at very low levels, whereas Indian hedgehog (Ihh) is expressed in the developing and mature retinal pigmented epithelium, beginning at embryonic day 13. To determine whether hedgehog proteins have activities on developing retinal cells, we used an in vitro system in which much of retinal histogenesis is recapitulated. 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. We found that SHH-N caused a transient increase in the number of retinal progenitor cells, and a 2- to 10-fold increase in the number of photoreceptors differentiating in the cultures when analyzed with three different photoreceptor-specific antigens. In contrast, the numbers of retinal ganglion cells and amacrine cells were similar to those in control cultures. These results show that Hedgehog proteins can regulate mitogenesis and photoreceptor differentiation in the vertebrate retina, and Ihh is a candidate factor from the pigmented epithelium to promote retinal progenitor proliferation and photoreceptor differentiation.

Animals↗
PubMed2004

Hedgehog: an unusual signal transducer.

Hedgehog proteins are of pivotal importance for development and maintenance of tissue patterns in adult organisms. Despite the role of Hedgehogs in differentiation and tumorigenesis, signal transduction of Hedgehog remains a relatively uncharted area of signalling biochemistry. For proper Hedgehog distribution into tissues, two highly unusual covalent modifications are necessary, palmitoylation of a secreted protein and the attachment of a cholesterol group, making Hedgehog the only established sterolated protein in nature. Hedgehog exerts its function via two membrane-bound receptors, Patched and Smoothened; presumably, Patched transports a cholesterol derivate out of cells which inhibits Smoothened. Binding of Hedgehog to Patched impedes this proposed pump function and thus Inhibition of Smoothened, which leads to expression of genetic Hedgehog targets via relief of transcriptional repression. These atypical features make Hedgehog physiology unique in biology and may explain why this field has attracted such significant attention.

Animals↗
PubMed1996

Sonic hedgehog differentially regulates expression of GLI and GLI3 during limb development.

Sonic hedgehog is a secreted factor regulating patterning of the anterior-posterior axis in the developing limb. The signaling pathway mediating the transduction of the signal is still poorly understood. In Drosophila several genes are known to act downstream of hedgehog, the fly homolog of Sonic hedgehog. An important gene epistatic to hedgehog is cubitus interruptus, which encodes the fly homolog of a family of vertebrate putative transcription factors, the GLI genes. We have isolated two members of the GLI family from chick, called GLI and GLI3. Their expression patterns in a variety of tissues during embryogenesis suggest that these genes may be targets of the Sonic hedgehog signal. We demonstrate that the two GLI genes are differentially regulated by Sonic hedgehog during limb development. Sonic hedgehog up-regulates GLI transcription, while down-regulating GLI3 expression in the mesenchymal cells of the developing limb bud. Finally, we demonstrate that an activated form of GLI can induce expression of Patched, a known target of Sonic hedgehog, thus implicating GLI as a key transcription factor in the vertebrate hedgehog signaling pathway. In conjunction with evidence from a mouse Gli3 mutant, our data suggest that GLI and GLI3 may have taken two different functions of their Drosophila homolog cubitus interruptus.

Animals↗
PubMed2001

An acylatable residue of Hedgehog is differentially required in Drosophila and mouse limb development.

The Drosophila Hedgehog protein and its vertebrate counterpart Sonic hedgehog are required for a wide variety of patterning events throughout development. Hedgehog proteins are secreted from cells and undergo autocatalytic cleavage and cholesterol modification to produce a mature signaling domain. This domain of Sonic hedgehog has recently been shown to acquire an N-terminal acyl group in cell culture. We have investigated the in vivo role that such acylation might play in appendage patterning in mouse and Drosophila; in both species Hedgehog proteins define a posterior domain of the limb or wing. A mutant form of Sonic hedgehog that cannot undergo acylation retains significant ability to repattern the mouse limb. However, the corresponding mutation in Drosophila Hedgehog renders it inactive in vivo, although it is normally processed. Furthermore, overexpression of the mutant form has dominant negative effects on Hedgehog signaling. These data suggest that the importance of the N-terminal cysteine of mature Hedgehog in patterning appendages differs between species.

Acylation↗
PubMed1994

Hedgehog is a signaling protein with a key role in patterning Drosophila imaginal discs.

The segment polarity genes hedgehog and engrailed are expressed in identical posterior-compartment-specific patterns in both Drosophila embryos and imaginal discs. We show here that the hedgehog protein is secreted, and it can cross embryo parasegment borders and the anterior-posterior compartment border of imaginal discs to neighboring cells that express neither engrailed nor hedgehog. In these cells, it is localized in discrete punctate structures that are sequestered within the polarized epithelium. Analysis of animals that have expressed hedgehog ectopically, or of a mutant that expresses hedgehog abnormally in the anterior compartment of the wing disc, indicates that hedgehog is involved in regulating patched. In the embryo, hedgehog regulation of patched apparently facilitates patched and wingless expression. In the discs, hedgehog regulation of patched and other genes in the anterior compartment helps to establish the proximodistal axis. We propose that the cell-cell communication mediated by hedgehog links the special properties of compartment borders with specification of the proximodistal axis in imaginal development.

Animals↗
PubMed2006

The SCL 3' enhancer responds to Hedgehog signaling during hemangioblast specification.

OBJECTIVE: The Hedgehog family of intercellular proteins has a crucial role in embryonic development. Recent experimental data suggests that the Hedgehog pathway may play a role in early hematopoiesis and angiogenesis. Stem cell leukemia (SCL), a basic helix-loop-helix (bHLH) transcription factor, is essential for the specification and function of the hemangioblast. SCL expression in early hematopoietic precursors and endothelium is directed by a 3' enhancer. We hypothesized that the SCL 3' enhancer is regulated by Hedgehog signaling during specification of mesoderm towards hemangioblastic fate. MATERIALS AND METHODS: Whole embryos derived from transgenic mouse lines carrying reporter genes under the regulation of SCL 3' enhancer were cultured in the presence of active Hedgehog peptide. Hedgehog transcriptional regulation of SCL 3' enhancer was studied by in vitro and in vivo binding and reporter assays. RESULTS: Hedgehog induced expansion of cells in which the SCL 3' enhancer was transcriptionally activated. A Gli-binding site within the 3' enhancer of SCL was identified and Gli1 was demonstrated to bind and transactivate this enhancer in a sequence-dependent manner. We further demonstrated that the core region of the SCL 3' enhancer is transcriptionally regulated by Hedgehog in-vivo and that the Gli-binding site located in this enhancer is essential for Hedgehog transcriptional regulation in vitro. CONCLUSION: These findings suggest that SCL may be a direct target of Hedgehog signaling during hemangioblast specification.

Animals↗
PubMed2005

Hedgehog signaling regulates expansion of pancreatic epithelial cells.

Embryonic Hedgehog signaling is essential for proper tissue morphogenesis and organ formation along the developing gastrointestinal tract. Hedgehog ligands are expressed throughout the endodermal epithelium at early embryonic stages but excluded from the region that will form the pancreas. Ectopic activation of Hedgehog signaling at the onset of pancreas development has been shown to inhibit organ morphogenesis. In contrast, Hedgehog signaling components are found within pancreatic tissue during subsequent stages of development as well as in the mature organ, indicating that a certain level of pathway activation is required for normal organ development and function. Here, we ectopically activate the Hedgehog pathway midway through pancreas development via expression of either Sonic (Shh) or Indian Hedgehog (Ihh) under control of the human Pax4-promoter. Similar pancreatic defects are observed in both Pax4-Shh and Pax4-Ihh transgenic lines, suggesting that regulation of the overall level of Hedgehog activity is critical for proper pancreas development. We also show that Hedgehog signaling controls mesenchymal vs. epithelial tissue differentiation and that pathway activation impairs formation of epithelial progenitors. Thus, tight control of Hedgehog pathway activity throughout embryonic development ensures proper pancreas organogenesis.

Animals↗
PubMed2000

Regular articles: conditional disruption of hedgehog signaling pathway defines its critical role in hair development and regeneration.

Members of the vertebrate hedgehog family (Sonic, Indian, and Desert) have been shown to be essential for the development of various organ systems, including neural, somite, limb, skeletal, and for male gonad morphogenesis. Sonic hedgehog and its cognate receptor Patched are expressed in the epithelial and/or mesenchymal cell components of the hair follicle. Recent studies have demonstrated an essential role for this pathway in hair development in the skin of Sonic hedgehog null embryos. We have further explored the role of the hedgehog pathway using anti-hedgehog blocking monoclonal antibodies to treat pregnant mice at different stages of gestation and have generated viable offspring that lack body coat hair. Histologic analysis revealed the presence of ectodermal placode and primodium of dermal papilla in these mice, yet the subsequent hair shaft formation was inhibited. In contrast, the vibrissae (whisker) development appears to be unaffected upon anti-hedgehog blocking monoclonal antibody treatment. Strikingly, inhibition of body coat hair morphogenesis also was observed in mice treated postnatally with anti-hedgehog monoclonal antibody during the growing (anagen) phase of the hair cycle. The hairless phenotype was reversible upon suspension of monoclonal antibody treatment. Taken together, our results underscore a direct role of the Sonic hedgehog signaling pathway in embryonic hair follicle development as well as in subsequent hair cycles in young and adult mice. Our system of generating an inducible and reversible hairless phenotype by anti-hedgehog monoclonal antibody treatment will be valuable for studying the regulation and mechanism of hair regeneration.

Animals↗
PubMed1996

Phosphorylation of the fused protein kinase in response to signaling from hedgehog.

The hedgehog gene (hh) of Drosophila melanogaster exerts both short- and long-range effects on cell patterning during development. The product of hedgehog is a secreted protein that apparently acts by triggering an intra-cellular signaling pathway, but little is known about the details of that pathway. The Drosophila gene fused (fu) encodes a serine/threonine-protein kinase that genetic experiments have implicated in signaling initiated by hedgehog. Here we report that the fused protein is phosphorylated during the course of Drosophila embryogenesis, as a result of hedgehog activity. In cell culture, phosphorylation of fused protein occurs in response to the biologically active form of hedgehog and cannot be blocked by activation of protein kinase A, which is thought to be an antagonist of signaling from hedgehog. These results suggest that fused and protein kinase A function downstream of hedgehog but in parallel pathways that eventually converge distal to fused. The reconstruction of signaling from hedgehog in cell culture should provide further access to the mechanisms by which hedgehog acts.

Animals↗
PubMed2006

Activation of the hedgehog pathway in human hepatocellular carcinomas.

Liver cancers, the majority of which are hepatocellular carcinomas (HCCs), rank as the fourth in cancer mortality worldwide and are the most rapidly increasing type of cancer in the United States. However, the molecular mechanisms underlying HCC development are not well understood. Activation of the hedgehog pathway is shown to be involved in several types of gastrointestinal cancers. Here, we provide evidence to indicate that hedgehog signaling activation occurs frequently in HCC. We detect expression of Shh, PTCH1 and Gli1 in 115 cases of HCC and in 44 liver tissues adjacent to the tumor. Expression of Shh is detectable in about 60% of HCCs examined. Consistent with this, hedgehog target genes PTCH1 and Gli1 are expressed in over 50% of the tumors, suggesting that the hedgehog pathway is frequently activated in HCCs. Of five cell lines screened, we found Hep3B, Huh7 and PLC/PRF/5 cells with detectable hedgehog target genes. Specific inhibition of hedgehog signaling in these three cell lines by smoothened (SMO) antagonist, KAAD-cyclopamine, or with Shh neutralizing antibodies decreases expression of hedgehog target genes, inhibits cell growth and results in apoptosis. In contrast, no effects are observed after these treatments in HCC36 and HepG2 cells, which do not have detectable hedgehog signaling. Thus, our data indicate that hedgehog signaling activation is an important event for development of human HCCs.

Carcinoma, Hepatocellular↗
PubMed1997

Axial (HNF3beta) and retinoic acid receptors are regulators of the zebrafish sonic hedgehog promoter.

The signalling molecule Sonic hedgehog is involved in a multitude of distinct patterning processes during vertebrate embryogenesis. In the nascent body axis of the zebrafish embryo, sonic hedgehog is co-expressed with axial (HNF3beta in mammals), a transcription regulator of the winged helix family. We show here that misexpression of axial leads to ectopic activation of sonic hedgehog expression in the zebrafish, suggesting that axial is a regulator of sonic hedgehog transcription. The sonic hedgehog gene was cloned from zebrafish and its promoter was characterized with respect to activation by axial. Expression of axial or rat HNF3beta in HeLa cells results in activation of co-transfected sonic hedgehog promoter-CAT fusion genes. This effect is mediated by two Axial (HNF3beta) recognition sequences. We furthermore identified a retinoic acid response element (RARE) in the sonic hedgehog upstream region which can be bound by retinoic acid receptor (RAR) and retinoid X receptor (RXR) heterodimers in vitro and confers retinoic acid inducibility to the sonic hedgehog promoter in the HeLa cell system. Our results suggest that both Axial (HNF3beta) and retinoic acid receptors are direct regulators of the sonic hedgehog gene.

Animals↗
PubMed2003

A novel function for Hedgehog signalling in retinal pigment epithelium differentiation.

Sonic hedgehog is involved in eye field separation along the proximodistal axis. We show that Hh signalling continues to be important in defining aspects of the proximodistal axis as the optic vesicle and optic cup mature. We show that two other Hedgehog proteins, Banded hedgehog and Cephalic hedgehog, related to the mouse Indian hedgehog and Desert hedgehog, respectively, are strongly expressed in the central retinal pigment epithelium but excluded from the peripheral pigment epithelium surrounding the ciliary marginal zone. By contrast, downstream components of the Hedgehog signalling pathway, Gli2, Gli3 and X-Smoothened, are expressed in this narrow peripheral epithelium. We show that this zone contains cells that are in the proliferative state. This equivalent region in the adult mammalian eye, the pigmented ciliary epithelium, has been identified as a zone in which retinal stem cells reside. These data, combined with double labelling and the use of other retinal pigment epithelium markers, show that the retinal pigment epithelium of tadpole embryos has a molecularly distinct peripheral to central axis. In addition, Gli2, Gli3 and X-Smoothened are also expressed in the neural retina, in the most peripheral region of the ciliary marginal zone, where retinal stem cells are found in Xenopus, suggesting that they are good markers for retinal stem cells. To test the role of the Hedgehog pathway at different stages of retinogenesis, we activated the pathway by injecting a dominant-negative form of PKA or blocking it by treating embryos with cyclopamine. Embryos injected or treated at early stages display clear proximodistal defects in the retina. Interestingly, the main phenotype of embryos treated with cyclopamine at late stages is a severe defect in RPE differentiation. This study thus provides new insights into the role of Hedgehog signalling in the formation of the proximodistal axis of the eye and the differentiation of retinal pigment epithelium.

Animals↗
PubMed2003

Combined activities of hedgehog signaling inhibitors regulate pancreas development.

Hedgehog signaling is known to regulate tissue morphogenesis and cell differentiation in a dose-dependent manner. Loss of Indian hedgehog (Ihh) results in reduction in pancreas size, indicating a requirement for hedgehog signaling during pancreas development. By contrast, ectopic expression of sonic hedgehog (Shh) inhibits pancreatic marker expression and results in transformation of pancreatic mesenchyme into duodenal mesoderm. These observations suggest that hedgehog signaling activity has to be regulated tightly to ensure proper pancreas development. We have analyzed the function of two hedgehog inhibitors, Hhip and patched 1 (Ptch), during pancreas formation. Our results indicated that loss of Hhip results in increased hedgehog signaling within the pancreas anlage. Pancreas morphogenesis, islet formation and endocrine cell proliferation is impaired in Hhip mutant embryos. Additional loss of one Ptch allele in Hhip-/-Ptch+/- embryos further impairs pancreatic growth and endodermal cell differentiation. These results demonstrate combined requirements for Hhip and Ptch during pancreas development and point to a dose-dependent response to hedgehog signaling within pancreatic tissue. Reduction of Fgf10 expression in Hhip homozygous mutants suggests that at least some of the observed phenotypes result from hedgehog-mediated inhibition of Fgf signaling at early stages.

Animals↗
PubMed1998

Control of somite patterning by Sonic hedgehog and its downstream signal response genes.

In the avian embryo, previous work has demonstrated that the notochord provides inductive signals to activate myoD and pax1 regulatory genes, which are expressed in the dorsal and ventral somite cells that give rise to myotomal and sclerotomal lineages. Here, we present bead implantation and antisense inhibition experiments that show that Sonic hedgehog is both a sufficient and essential notochord signal molecule for myoD and pax1 activation in somites. Furthermore, we show that genes of the Sonic hedgehog signal response pathway, specifically patched, the Sonic hedgehog receptor, and gli and gli2/4, zinc-finger transcription factors, are activated in coordination with somite formation, establishing that Sonic hedgehog response genes play a regulatory role in coordinating the response of somites to the constitutive notochord Sonic hedgehog signal. Furthermore, the expression of patched, gli and gli2/4 is differentially patterned in the somite, providing mechanisms for differentially transducing the Sonic hedgehog signal to the myotomal and sclerotomal lineages. Finally, we show that the activation of gli2/4 is controlled by the process of somite formation and signals from the surface ectoderm, whereas upregulation of patched and activation of gli is controlled by the process of somite formation and a Sonic hedgehog signal. The Sonic hedgehog signal response genes, therefore, have important functions in regulating the initiation of the Sonic hedgehog response in newly forming somites and in regulating the patterned expression of myoD and pax1 in the myotomal and sclerotomal lineages following somite formation.

Amino Acid Sequence↗