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PubMed1995

Positional signaling by hedgehog in Drosophila imaginal disc development.

We describe a dominant gain-of-function allele of the segment polarity gene hedgehog. This mutation causes ectopic expression of hedgehog mRNA in the anterior compartment of wing discs, leading to overgrowth of tissue in the anterior of the wing and partial duplication of distal wing structures. The posterior compartment of the wing is unaffected. Other imaginal derivatives are affected, resulting in duplications of legs and antennae and malformations of eyes. In mutant imaginal wing discs, expression of the decapentaplegic gene, which is implicated in the hedgehog signaling pathway, is also perturbed. The results suggest that hedgehog protein acts in the wing as a signal to instruct neighboring cells to adopt fates appropriate to the region of the wing just anterior to the compartmental boundary.

Alleles↗
PubMed1998

Hedgehog family member is expressed throughout regenerating and developing limbs.

Members of the hedgehog family have been shown to play a key role in many developmental processes, including limb patterning and chondrogenesis. We have therefore investigated whether members of this family are also expressed during regeneration of the adult urodele limb and are regulated by retinoic acid (RA), since this derivative induces proximodistal duplications in regenerating limbs, and has been shown to regulate sonic hedgehog (shh) in the developing limbs of birds and mammals. We report here that a newt homologue of Xenopus banded hedgehog, called N-bhh, is uniformly expressed by mesenchymal blastemal cells from the initial stages of regeneration and is up-regulated by RA. In addition, we show that N-bhh is uniformly expressed in the early limb bud of the newt embryo. Since bhh has not been detected in developing limbs of higher vertebrates, its expression in developing and regenerating newt limbs may be related to the regenerative capability of urodeles.

Amino Acid Sequence↗
PubMed2001

The Hedgehog signalling pathway and cancer.

The Hedgehog signalling pathway is important in embryological development and is highly conserved through evolution. Recently Patched, a member of the pathway, was found to be important in Gorlin's syndrome. Inherited Patched gene mutations underlie the syndrome, in which a key feature is multiple basal cell carcinomas (BCCs). The gene is also mutated in sporadic BCCs as well as in sporadic occurrences of other tumours seen in Gorlin's syndrome. The precise mechanism whereby Patched gene mutation leads to tumour development is not known, but BCC is characterized by relentless local invasion and only rarely metastasizes. This suggests that abnormalities of the Hedgehog pathway account for these features. This proposal is discussed in the context of what is already known about the normal function of the Hedgehog pathway and its deregulation in cancer.

Basal Cell Carcinoma↗
PubMed2004

Organization of the main olfactory bulbs of some mammals: musk shrews, moles, hedgehogs, tree shrews, bats, mice, and rats.

We immunohistochemically examined the organization of the main olfactory bulbs (MOBs) in seven mammalian species, including moles, hedgehogs, tree shrews, bats, and mice as well as laboratory musk shrews and rats. We focused our investigation on two points: 1) whether nidi, particular spheroidal synaptic regions subjacent to glomeruli, which we previously reported for the laboratory musk shrew MOBs, are also present in other animals and 2) whether the compartmental organization of glomeruli and two types of periglomerular cells we proposed for the rat MOBs are general in other animals. The general laminar pattern was similar among these seven species, but discrete nidi and the nidal layer were recognized only in two insectivores, namely, the mole and laboratory musk shrew. Olfactory marker protein-immunoreactive (OMP-IR) axons extended beyond the limits of the glomerular layer (GL) into the superficial region of the external plexiform layer (EPL) or the nidal layer in the laboratory musk shrew, mole, hedgehog, and tree shrew but not in bat, mouse, and rat. We observed, in nidi and the nidal layer in the mole and laboratory musk shrew MOBs, only a few OMP-IR axons. In the hedgehog, another insectivore, OMP-IR processes extending from the glomeruli were scattered and intermingled with calbindin D28k-IR cells at the border between the GL and the EPL. In the superficial region of the EPL of the tree shrew MOBs, there were a small number of tiny glomerulus-like spheroidal structures where OMP-IR axons protruding from glomeruli were intermingled with dendritic branches of surrounding calbindin D28k-IR cells. Furthermore, we recognized the compartmental organization of glomeruli and two types of periglomerular cells in the MOBs of all of the mammals we examined. These structural features are therefore considered to be common and important organizational principles of the MOBs.

Animals↗
PubMed1986

Structure of the olfactory bulb of the hedgehog (Erinaceus europaeus): description of cell types in the granular layer.

The cytoarchitecture of the olfactory bulb and the cell types in the granular layer of adult hedgehogs have been studied with the Golgi method. The mitral cell layer does not stand out as a monolayer as in most mammals; it is arranged as a diffuse stratum with mitral cells displaced into the external plexiform layer. The external plexiform layer is exceedingly thick and contains the branches of peripheral processes of granule cells and displaced mitral and tufted cells. The granular layer contains granule cells and varieties of short-axon cells. Among granule cells a type of cell with an elaborate system of protrusions close to the cell body has been found. Four main varieties of short-axon cells are described. These include cells with local or extended axons, according to the branching pattern of their axons inside the granular layer or extending into the external plexiform layer as well. Short-axon cells were also classified as cells with smooth and spinous dendrites. A variety of cell with smooth dendrites and elaborate axonal system reaching the periglomerular zone is described. This type of cell has been found frequently in the olfactory bulb of the hedgehog. In comparison to several other mammals, short-axon cells in the olfactory bulb of the hedgehog have been found to be particularly abundant and to have more complex axonal systems. It is suggested that some of them may represent inhibitory interneurons acting upon granule and periglomerular cells, playing an important role in the centrifugal pathway controlling the olfactory input.

Animals↗
PubMed2004

Indian hedgehog and syndecans-3 coregulate chondrocyte proliferation and function during chick limb skeletogenesis.

Hedgehog proteins exert critical roles in embryogenesis and require heparan sulfate proteoglycans (HS-PGs) for action. Indian hedgehog (Ihh) is produced by prehypertrophic chondrocytes in developing long bones and regulates chondrocyte proliferation and other events, but it is not known whether it requires HS-PGs for function. Because the HS-PG syndecan-3 is preferentially expressed by proliferating chondrocytes, we tested whether it mediates Ihh action. Primary chick chondrocyte cultures were treated with recombinant Ihh (rIhh-N) in absence or presence of heparinase I or syndecan-3 neutralizing antibodies. While rIhh-N stimulated proliferation in control cultures, it failed to do so in heparinase- or antibody-treated cultures. In reciprocal gain-of-function studies, chondrocytes were made to overexpress syndecan-3 by an RCAS viral vector. Cells became more responsive to rIhh-N, but even this response was counteracted by heparinase or antibody treatment. To complement the in vitro data, RCAS viral particles were microinjected in day 4-5 chick wing buds and effects of syndecan-3 misexpression were monitored over time. Syndecan-3 misexpression led to widespread chondrocyte proliferation and, interestingly, broader expression and distribution of Ihh. In addition, the syndecan-3 misexpressing skeletal elements were short, remained cartilaginous, lacked osteogenesis, and exhibited a markedly reduced expression of collagen X and osteopontin, products characteristic of hypertrophic chondrocytes and bone cells. The data are the first to indicate that Ihh action in chondrocyte proliferation involves syndecan-3 and to identify a specific member of the syndecan family as mediator of hedgehog function.

Animals↗
PubMed1996

cAMP, an activator of protein kinase A, suppresses the expression of sonic hedgehog.

In Drosophila, it has been shown that protein kinase A and hedgehog have antagonistic actions during the formation of imaginal disks. In vertebrate skin, sonic hedgehog is expressed specifically in the feather bud epithelia. using an in vitro explant culture model we showed that dibutyryl cAMP, a protein kinase A (PKA) activator, suppresses the expression of Sonic hedgehog, (Shh) and continuous feather growth. The results suggest that Shh and PKA also have antagonistic action during vertebrate skin morphogenesis.

Animals↗
PubMed2000

Erythroid differentiation in vitro is blocked by cyclopamine, an inhibitor of hedgehog signaling.

Adult hematopoietic differentiation is a developmental process that employs many of the same molecular mechanisms as embryogenesis. To explore the possibility that hedgehog signaling is involved in the control of hematopoietic differentiation, we screened a panel of human leukemia cell lines for the expression of Patched1 and Smoothened, the receptor and coreceptor for hedgehog ligands. Expression was found in multiple cell lines, and Patched1 expression was detected in normal marrow. Induction of myeloid differentiation in cell lines downregulated expression of both genes. When normal marrow mononuclear cells were grown in semisolid medium in the presence of 10 microM cyclopamine, development of colonies of granulocytic/monocytic lineage was unaffected in terms of both number and morphology. The number of erythroid colonies, however, was significantly reduced (P < 0.01). Furthermore, hemoglobinization was substantially delayed relative to controls in those erythroid colonies that did form. Incubation of hematopoietic progenitors with Shh-N and GM-CSF resulted in increased granulocyte/monocyte colonies (P < 0.01); the increase was blocked by cyclopamine. Incubation of hematopoietic progenitors with Shh-N and stem cell factor resulted in larger erythroid colonies. These results suggest that elements of the hedgehog signaling pathway are involved in the control of hematopoietic differentiation.

Cell Differentiation↗
PubMed1995

Hedgehog and Bmp genes are coexpressed at many diverse sites of cell-cell interaction in the mouse embryo.

The mouse Hedgehog gene family consists of three members, Sonic, Desert, and Indian hedgehog (Shh, Dhh, and Ihh, respectively), relatives of the Drosophila segment polarity gene, hedgehog (hh). All encode secreted proteins implicated in cell-cell interactions. One of these, Shh, is expressed in and mediates the signaling activities of several key organizing centers which regulate central nervous system, limb, and somite polarity. However, nothing is known of the roles of Dhh or Ihh, nor of the possible function of Shh during later embryogenesis. We have used serial-section in situ hybridization to obtain a detailed profile of mouse Hh gene expression from 11.5 to 16.5 days post coitum. Apart from the gut, which expresses both Shh and Ihh, there is no overlap in the various Hh expression domains. Shh is predominantly expressed in epithelia at numerous sites of epithelial-mesenchymal interactions, including the tooth, hair, whisker, rugae, gut, bladder, urethra, vas deferens, and lung, Dhh in Schwann and Sertoli cell precursors, and Ihh in gut and cartilage. Thus, it is likely that Hh signaling plays a central role in a diverse array of morphogenetic processes. Furthermore, we have compared Hh expression with that of a second family of signaling molecules, the Bone morphogenetic proteins (Bmps), vertebrate relatives of decapentaplegic, a target of the Drosophila Hh signaling pathway. The frequent expression of Bmp-2, -4, and -6 in similar or adjacent cell populations suggests a conserved role for Hh/Bmp interactions in vertebrate development.

Animals↗
PubMed1996

Inhibition of protein kinase A phenocopies ectopic expression of hedgehog in the CNS of wild-type and cyclops mutant embryos.

The zebrafish hedgehog (hh) family members tiggy-winkle hedgehog (twhh) and sonic hedgehog (shh) are involved in patterning the ventral CNS and proximal eye. Using a dominant negative protein kinase A regulatory subunit mutant, we show that these hh activities are mediated by protein kinase A. The effects of dominant negative protein kinase A on pax2 expression appear to be cell nonautonomous, suggesting that cells can respond to regulation of hh signaling by modulating an additional cell-cell signaling pathway. We also investigate the potential involvement of cyclops in the hh signaling pathway and conclude that although cyclops mutant cells can respond to hh signaling, neither hh nor dominant negative protein kinase A rescues the phenotypes associated with cyclops.

Animals↗
PubMed2000

A gain-of-function mutant of patched dissects different responses to the hedgehog gradient.

The Hedgehog (Hh) signal has an inductive role during Drosophila development. Patched is part of the Hedgehog-receptor complex and shows a repressive function on the signaling cascade, which is alleviated in the presence of Hh. Herein, we identify the first dominant gain-of-function allele of patched, Confused (patched(Con)). Analysis of the patched(Con) allele led us to uncover novel features of the reception and function of the Hh signal. At least three different regions of gene expression were identified and a gradient of cell affinities was established in response to Hh. A new state of Cubitus interruptus activity responsible for the activation of araucan and caupolican genes of the iroquois complex, independent of Fused kinase function, was shown. In the disc, patched(Con) behaved like fused mutants and was rescued by Suppressor of fused mutations. However, fused mutants are embryonic lethal while patched(Con) is not, suggesting that Patched could interpret Hedgehog signaling differently in the embryo and in the adult.

Alleles↗
PubMed2002

Sonic hedgehog is required early in pancreatic islet development.

Pancreatic organogenesis relies on a complex interplay of cell-autonomous and extracellular signals. We demonstrate that the morphogen sonic hedgehog (Shh) is required for pancreatic development in zebrafish. Genetic mutants of Shh and its signaling pathway establish this dependence as specific to endocrine, but not exocrine, pancreas. Using cyclopamine to inhibit hedgehog signaling, we show that transient Shh signaling is necessary during gastrulation for subsequent differentiation of endoderm into islet tissue. A second hedgehog-dependent activity occurring later in development was also identified and may be analogous to the known action of Shh in gut endoderm to direct localization of pancreatic development. The early action of Shh may be part of a more general process allowing neuroendocrine cells to originate in nonneuroectodermally derived tissues.

Animals↗
PubMed2002

Intrastriatal injection of sonic hedgehog reduces behavioral impairment in a rat model of Parkinson's disease.

Sonic hedgehog (Shh), a member of hedgehog (hh) family of signaling molecules, is necessary for normal axial patterning and cellular differentiation in the developing central nervous system. Shh also promotes the survival of fetal dopaminergic neurons and protects cultures of fetal midbrain dopaminergic neurons from the toxic effects of N-methyl-4-phenylpyridinium (MPP(+)), a neurotoxin that selectively injures nigral dopaminergic neurons. The mRNA expression of Shh and its putative receptor in the adult brain indicates an important role of Shh in the mature nervous system in addition to its roles during embryogenesis. In this study we examined the behavioral and anatomical effects of intrastriatal injection of singly myristoylated wild-type human Sonic hedgehog N-terminal fragment (Shh-M) in a rat model of Parkinson's disease (PD). Five groups of rats received a series of four intrastriatal injections of Shh-M (180 ng, 540 ng, or 4.275 microg per injection), glial cell line-derived neurotrophic factor (GDNF) (1 microg/injection), or vehicle on days 1, 3, 5, and 8. On day 4, the animals received an intrastriatal injection of 15 microg 6-hydroxydopamine (6-OHDA) free base. Intrastriatal administration of Shh (180 ng/injection) twice before and after a single intrastriatal injection of 6-OHDA reduced apomorphine- and amphetamine-induced rotation and forelimb akinesia and partially preserved dopaminergic axons in the striatum. This is the first demonstration in vivo that Shh reduces behavioral deficits induced by intrastriatal 6-OHDA lesion and suggests that Shh may be useful in the treatment of disorders that affect the nigrostriatal system, such as PD.

Amphetamine↗
PubMed1991

The karyotype of the middle-African hedgehog Atelerix albiventris Wagner, 1841 and its cytotaxonomical relationships to other Erinaceinae (Insectivora: Erinaceidae).

Like other hedgehog species investigated hitherto, also the Middle African species Atelerix albiventris has a diploid number of 48 chromosomes. However, Aethechinus and Atelerix display quite distinct cytogenetic characteristics compared to the hedgehog genera Erinaceus, Hemiechinus and Paraechinus. Individual chromosome structures and reactivities permit the recognition of similarities to the Algerian hedgehog Aethechinus algirus and indicate their close relationship. Nevertheless, the proposal by Corbet (1988) to merge the two taxa into one genus, which is contrary to Robbins and Setzer (1985) remains to be clarified by further investigations.

Animals↗
PubMed1995

Sequence analysis of the complete mitochondrial DNA molecule of the hedgehog, Erinaceus europaeus, and the phylogenetic position of the Lipotyphla.

The sequence of the mitochondrial DNA (mtDNA) molecule of the European hedgehog (Erinaceus europaeus) was determined. The length of the sequence presented is 17,442 nucleotides (nt). The molecule is thus the largest eutherian mtDNA molecule so far reported. The organization of the molecule conforms with that of other eutherians, but the control region of the molecule is exceptionally long, 1,988 nt, due to the presence of repeated motifs at two different positions in the 3' part of the control region. The length of the control region is not absolute due to pronounced heteroplasmy caused by variable numbers of the motif TACGCA in one of the repetitive regions. The sequence presented includes 46 repeats of this type. The other repeated region is composed of different AT-rich repeats. This region was identical among four clones studied. Comparison of mitochondrial peptide-coding genes identified a separate position of the hedgehog among several mammalian orders. The concatenated protein sequence of the 13 peptide-coding genes was used in a phylogenetic study using the opossum as outgroup. The position of the hedgehog sequence was basal among the other eutherian sequences included: human, rat, mouse, cow, blue whale, harbor seal, and horse. The analysis did not resolve the relationship among carnivores, perissodactyls, and artiodactyls/cetaceans, suggesting a closer relationship among these orders than acknowledged by classical approaches.

Animals↗
PubMed1986

Neocortical layers I and II of the hedgehog (Erinaceus europaeus). II. Thalamo-cortical connections.

This study examines the thalamo-cortical projections to the most superficial neocortical layers in the hedgehog (Erinaceus europaeus) after small injections of horseradish peroxidase and horseradish peroxidase conjugated to wheat germ agglutinin in the somato-sensory cortex. The injections were limited to layers I, II and upper parts of layer III/IV. Retrogradely labeled cells were plotted in serial sections through the thalamus. Injections in the somato-sensory cortex gave a pattern of elongated columns of labeled cells, extending rostro-caudally in the nucleus ventralis thalami. In the neocortex, labeled fibers extended for considerable distances running horizontally in layer I. Complementary observations demonstrate the thalamic origin of certain, coarse ascending bundles observed previously in Golgi preparations of the hedgehog. It is concluded that a major cortical input to layer I originates in the hedgehog in the principal thalamic (relay) nuclei. After injections in the somato-sensory cortex, retrogradely labeled cells were also found in the nucleus ventro-medialis thalami and very few in a zone medial to the nucleus ventralis thalami corresponding to the intralaminar thalamic nuclei. The contributions of this latter system seem to be limited in comparison with other mammals.

Animals↗
PubMed1995

Protein and lipid utilization during fasting with shallow and deep hypothermia in the European hedgehog (Erinaceus europaeus).

We investigated whether the relative contributions of body protein and lipid reserves differ according to the level of energy expenditure in fasting animals. Protein and lipid utilization was therefore quantified and compared in hedgehogs which fasted with shallow and deep hypothermia, i.e. by exposure at 5 or 20 degrees C ambient temperature. Body composition was determined for every 150-g decrease in mass throughout the experiment, allowing the calculation of regression lines between body mass (independent variable, x) and body composition (dependent variable, y: water, protein, neutral lipids, phospholipids and cholesterol). There were highly significant (P < 0.001) linear decreases in all body components with decreasing body mass in both groups of hedgehogs. Neutral lipids were the main component of the total body mass loss (54%) in fasted animals with shallow and deep hypothermia, percentages of water (26-30%) and protein (10-11%) being lower, and those of phospholipid and cholesterol negligible (< 0.5%). In spite of different levels in energy expenditure (2.54 and 1.07 W.kg-1 in shallow- and deep-hypothermal fasting hedgehogs, respectively), the energy sources were identical in both groups, neutral lipid being the main fuel (91-92%) and body protein accounting for the remainder (8-9%). Prolonged fasting with shallow and deep hypothermia were marked by low alaninemia and glycemia, while plasma free fatty acids and beta-hydroxybutyrate were elevated.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Hedgehog signaling in vertebrate and invertebrate limb patterning.

Invertebrate and vertebrate limbs have very different anatomies and modes of development. Despite these differences, recent studies demonstrate that a significant overlap exists in the signals used to pattern invertebrate and vertebrate limbs. One of these signaling molecules is Hedgehog, a secreted protein that functions to coordinate growth and proliferation along the anterior-posterior axis of developing limbs. Recent studies indicate that the mechanism of action, regulation and function of Hedgehog signaling in Drosophila and vertebrate limb development are often quite similar, yet at other times are distinct. Here we highlight the similarities and differences between the use of Hedgehog signaling in these two systems.

Animals↗