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PubMed2000

Hedgehog proteins stimulate chondrogenic cell differentiation and cartilage formation.

Sonic hedgehog (Shh) and Indian hedgehog (Ihh) are important regulators of skeletogenesis, but their roles in this complex multistep process are not fully understood. Recent studies have suggested that the proteins participate in the differentiation of chondrogenic precursor cells into chondrocytes. In the present study, we have tested this possibility more directly. We found that implantation of dermal fibroblasts expressing hedgehog proteins into nude mice induces ectopic cartilage and bone formation. Immunohistological and reverse-transcription polymerase chain reaction (RT-PCR) analyses revealed that the ectopic tissues derived largely if not exclusively from host cells. We found also that treatment of clonal prechondrogenic RMD-1 and ATDC5 cells in culture with Ihh or recombinant amino half of Shh (recombinant N-terminal portion of Shh [rShh-N]) induced their differentiation into chondrocytes, as revealed by cytoarchitectural changes, Alcian blue staining and proteoglycan synthesis. Induction of RMD-1 cell differentiation by Ihh or rShh-N was synergistically enhanced by cotreatment with bone morphogenetic protein 2 (BMP-2) but was blocked by cotreatment with fibroblast growth factor 2 (FGF-2). Our findings indicate that hedgehog proteins have the ability to promote differentiation of chondrogenic precursor cells and that their action in this process can be influenced and modified by synergistic or antagonist cofactors.

Animals↗
PubMed1988

Thermoregulation in the female hedgehog, Erinaceus europaeus, during the breeding season.

The body temperatures of 3 breeding and 7 non-breeding female hedgehogs were monitored during 3 years. Lactating females had significantly higher and less variable body temperatures than did pregnant and non-breeding hedgehogs. Breeding females had circadian body temperature cycles that were more biphasic than those of non-breeders. Females maintaining higher mean daily body temperatures showed less variability about the mean than those exhibiting lower mean daily body temperatures. The rate at which body temperatures became more variable as mean daily body temperatures fell was 4.6 times more rapid in non-breeding females than in pregnant and lactating hedgehogs. With the exception of a single female in late gestation, hedgehogs readily became torpid under conditions of low ambient temperature and short photoperiod during summer, particularly when their food intake was restricted.

Animals↗
PubMed1988

Seasonal endocrine cycles in the European hedgehog, Erinaceus europaeus.

Adult hedgehogs, maintained in captivity under natural environmental conditions of photoperiod and ambient temperature, were bled monthly. Plasma was assayed for melatonin, testosterone, prolactin, thyroxin, beta-endorphin and both plasma and urine for cortisol. Melatonin concentrations followed a circannual pattern, maximal between November and February at photoperiods less than 10L:14D, which is suggested as a key photoperiod. beta-Endorphin concentrations were maximal between March and September, coinciding with the reproductively active season of the hedgehog. Prolactin values were elevated during hibernation, indicating continued hypothalamo-pituitary axis activity. Testosterone and thyroxin levels were high between February and July and February and August respectively. During spring thyroxin concentrations rose 1 month later in females than males, reflecting the earlier arousal of the males from hibernation. There were no marked seasonal cycles of plasma or urinary cortisol. The results indicate photoperiod as the main factor in regulating hedgehog seasonality, with melatonin, beta-endorphin and prolactin important in the timing of reactivation of reproduction. Sexual differences in hedgehogs suggests environmental fine tuning of endogenous cycles, males being ready to inseminate females early in spring, while females only begin full breeding activity when conditions are suitable.

Animals↗
PubMed2001

Unilateral proptosis and orbital cellulitis in eight African hedgehogs (Atelerix albiventris).

Eight African hedgehogs (Atelerix albiventris) were presented with unilateral proptosis. Six animals presented specifically for an ocular problem, whereas two had concurrent neurologic disease. Enucleation and light microscopic examination of tissues was performed in five animals, and euthanasia followed by complete postmortem examination was performed in three animals. Histopathologic findings in all hedgehogs included orbital cellulitis, panophthalmitis, and corneal ulceration, with perforation in seven of eight eyes. The etiology of the orbital cellulitis was not determined, but it appeared to precede proptosis. Orbits in hedgehogs are shallow and the palpebral fissures are large, which may predispose them to proptosis, similar to brachycephalic dogs. This clinical presentation was seen in 15% (8/54) of African hedgehogs presented to the Western College of Veterinary Medicine over a 2-yr period from January 1995 to December 1996 and warrants further investigation.

Animals↗
PubMed2003

Distribution of Indian hedgehog and its receptors patched and smoothened in human chronic pancreatitis.

Indian hedgehog (IHH) and its receptors patched (PTC) and smoothened (SMO) belong to the hedgehog family of signaling molecules, which are essential for a variety of patterning events during mammalian tIssue development. IHH plays a role in pancreas organogenesis and differentiation, as well as in the regulation of insulin production. In the present study, the expression of IHH and its receptors was analyzed in normal human pancreatic and chronic pancreatitis (CP) tIssues using Northern blotting, immunohistochemistry and Western blotting, and was correlated with clinicopathological parameters. In addition, the effects of inhibition and stimulation of the hedgehog signaling pathway on cell growth were determined in TAKA-1 normal pancreatic ductal cells. IHH mRNA was expressed in the normal human pancreas and CP tIssues, with slightly higher expression levels in CP. Using immunohistochemistry, IHH and its receptors were localized mainly in the islet cells of the normal pancreas. In CP, IHH and its receptors were present in the cells forming tubular complexes and in the islets with a different signal pattern compared with the islets in the normal pancreas. Correlation between diabetic and non-diabetic CP patients revealed no significant difference in IHH, SMO, or PTC immunoreactivity. Inhibition of hedgehog signaling in TAKA-1 pancreatic ductal cells using cyclopamine significantly reduced their growth through cell cycle arrest, while stimulation of the IHH pathway enhanced the growth of these cells. In conclusion, IHH and its receptors are expressed in the normal human pancreas and in CP, yet with a different distribution and cellular localization. IHH signaling may be involved in the pathogenesis of CP, i.e. in the formation and proliferation of tubular complexes and in islet cell dysfunction.

Adult↗
PubMed2006

Nondestructive pollution exposure assessment in the European hedgehog (Erinaceus europaeus): III. Hair as an indicator of endogenous organochlorine compound concentrations.

Concentrations of organochlorine persistent pollutants were investigated in tissues of the European hedgehog (Erinaceus europaeus). Road kills and carcasses from wildlife rescue centers were used to characterize organochlorine compound tissue distribution and tissue profile dissimilarities (hair, liver, kidney, muscle, and adipose tissue). The most important contaminants were polychlorinated biphenyls (PCBs), chlordanes (CHLs), and DDTs, with median concentrations of 75, 5.1, and 1.4 ng/g liver wet weight, respectively. Median levels for the remaining compounds-hexachlorobenzene (HCB), hexachlorocyclohexanes (HCHs), and octachlorostyrene-were less than 0.5 ng/g liver wet weight. Compared to results with other mammalian wildlife, the present results indicate that hedgehogs may accumulate considerable concentrations of organochlorine compounds. Polychlorinated biphenyls and HCB preferably accumulated in liver and muscle tissue. Concentrations of DDTs and HCHs were highest in muscle tissue and hair, respectively. Octachlorostyrene and CHL levels were predominant in liver. The observed positive relationships between concentrations in hair and internal tissues for PCBs, DDTs, HCB, HCHs, and CHLs (0.49 < r < 0.91) and for several individual PCB, DDT, and CHL compounds (0.31 < r < 0.76) indicate the usefulness of hair as a biomonitoring tool of organochlorine compounds. Multivariate profile analyses revealed a higher dominance of less-persistent compounds (p,p'-DDT, alpha-HCH, and PCBs 95, 101, and 149) in hair compared to internal tissues. The present study demonstrates the suitability of hedgehog hair as a nondestructive biomonitoring tool regarding pollution with organochlorine compounds and the promising role of the hedgehog as a mammalian indicator species of pollution in terrestrial environments.

Adipose Tissue↗
PubMed2000

Hedgehog signaling regulation of insulin production by pancreatic beta-cells.

Hedgehogs (Hhs) are intercellular signaling molecules that regulate tissue patterning in mammalian development. Mammalian Hhs include Sonic hedgehog (Shh), Indian hedgehog (Ihh), and Desert hedgehog (Dhh). The absence of Shh expression is required for the early development of the endocrine and exocrine pancreas, but whether Hh signaling functions in the fully developed adult endocrine pancreas is unknown. Here we report that Hhs Ihh and Dhh and their receptors patched (Ptc) and smoothened are expressed in the endocrine islets of Langerhans of the fully developed rat pancreas and in the clonal gamma-cell line INS-1. We demonstrate the coexpression of Ptc with insulin in beta-cells of mouse pancreatic islets, indicating that beta-cells are targets of active Hh signaling. The administration of cyclopamine, a Hh signaling inhibitor, decreases both insulin secretion from and insulin content of INS-1 cells. The effects of Hh signaling on insulin production occur at the transcriptional level because activation of Hh signal transduction by ectopic expression of Shh increases rat insulin I promoter activation in a dose-dependent manner in transient transfections of INS-1 and MIN6 beta-cell lines. In contrast, inhibition of Hh signaling with increasing concentrations of cyclopamine progressively reduces insulin promoter activity. Furthermore, the treatment of INS-1 cells with cyclopamine diminishes endogenous insulin mRNA expression. We propose that Hh signaling is not restricted to patterning in early pancreas development but also continues to signal in differentiated beta-cells of the endocrine pancreas in regulating insulin production. Thus, defective Hh signaling in the pancreas should be considered as a potential factor in the pathogenesis of type 2 diabetes.

Animals↗
PubMed2007

Hedgehog signaling promotes medulloblastoma survival via Bc/II.

Activation of the Hedgehog (Hh) pathway has been identified in several cancers, including medulloblastoma, but the mechanisms by which this pathway affects tumor survival and growth are incompletely understood. We investigated whether Hedgehog might promote survival of medulloblastoma cells via up-regulation of BclII. We found that mRNA levels of the Hedgehog pathway effector Gli1 were significantly associated with BclII expression in medulloblastoma and that Gli1 and BclII are both present in regions of decreased apoptosis in nodular medulloblastoma. Transient overexpression of Gli1 and Gli2 in medulloblastoma cultures induced a BclII transcriptional reporter and increased BclII protein levels, whereas stable overexpression of Gli1 was associated with increased BclII mRNA. The Hedgehog antagonist cyclopamine blocked expression of the Hh pathway targets PTCH1 and Gli1, lowered BclII levels, and increased apoptosis in DAOY and UW228 medulloblastoma cells. Apoptotic induction caused by cyclopamine could be rescued in part by enforced expression of Gli1 or BclII. Hh pathway blockade also sensitized medulloblastoma to the effects of the proapoptotic agent lovastatin. These data demonstrate that BclII is an important mediator of Hh activity in medulloblastoma and suggest new strategies for combined chemotherapeutic regimens.

Apoptosis↗
PubMed2006

Multiple gene expression analyses in paraffin-embedded tissues by TaqMan low-density array: Application to hedgehog and Wnt pathway analysis in ovarian endometrioid adenocarcinoma.

Recent studies have shown the hedgehog and Wnt families of signaling proteins to be associated with tumor initiation, growth, and survival. However, these pathways remain unexplored in ovarian endometrioid adenocarcinoma (OEA). Here, we describe a novel TaqMan low-density array to examine the expression of 26 and 20 genes in the hedgehog and Wnt pathways, respectively, in six matched snap-frozen and formalin-fixed, paraffin-embedded (FPE) OEA specimens. Expression values were normalized to uninvolved ovarian epithelium. Gene expression in matched frozen and FPE tissues demonstrated significant concordance (r = 0.92, P < 0.0001). However, comparison of amplified and unamplified RNA from frozen OEA tissues revealed an altered molecular profile in amplified RNA. Amplification of RNA from FPE tissues was not successful. The expression of Desert hedgehog (DHH), Indian hedgehog (IHH), Hedge-hog interacting protein (HHIP), Wnt10B, Wnt9B, and Wnt inhibitory factor (WIF1) were tumor-specific with no detectable expression in normal ovarian epithelium. In addition, several genes were significantly (P < 0.025) down-regulated in OEA, including cyclin E2, Porcupine, c-Myc, and Axin 2 (4.8-, 3.6-, 2.9-, and 1.9-fold, respectively). TaqMan low-density array provides an effective multivariate technique for examining gene expression in RNA isolated from either snap-frozen or archival FPE tissues and can identify tumor-specific genes, possibly leading to novel treatments.

Animals↗
PubMed2006

Forelimb amputation for treatment of a peripheral nerve sheath tumor in an African pygmy hedgehog.

CASE DESCRIPTION: A 6-year-old female African pygmy hedgehog was evaluated because of a mass of unknown duration on the lateral aspect of the right shoulder region. CLINICAL FINDINGS: A fine-needle aspirate of the mass was collected for cytologic examination; findings were consistent with a spindle cell tumor. A CBC, plasma biochemical analyses, and whole-body radiography revealed no other abnormalities. TREATMENT AND OUTCOME: An initial surgery performed in an attempt to remove the mass with preservation of the limb failed in that tumor-free surgical margins were not obtained. Histologically, the mass was identified as a peripheral nerve sheath tumor (neurofibrosarcoma). A second surgery to amputate the forelimb was successful. After 1 year, there had been no further development of peripheral nerve sheath tumor at this or other sites. CLINICAL RELEVANCE: In African pygmy hedgehogs, potential differential diagnoses for a subcutaneous mass should include peripheral nerve sheath tumor. If necessary, forelimb amputation can be performed successfully in this species with procedures modified from those used in dogs. Information gathered during the treatment and recovery of the hedgehog of this report may assist practicing veterinarians in counseling owners of hedgehogs that are undergoing forelimb amputation with regard to the course of recovery that may be expected following this procedure.

Amputation, Surgical↗
PubMed2004

Chromosome 17p deletion in human medulloblastoma: a missing checkpoint in the Hedgehog pathway.

Although deregulation of Hedgehog signalling is considered to play a crucial oncogenic role and commonly occurrs in medulloblastoma, genetic lesions in components of this pathway are observed in a minority of cases. The recent identification of a novel putative tumor suppressor (REN(KCTD11)) on chromosome 17p13.2, a region most frequently lost in human medulloblastoma, highlights the role of allelic deletion of the gene in this brain malignancy, leading to the loss of growth inhibitory activity via suppression of Gli-dependent activation of Hedgehog target genes. The presence on 17p13 of another tumor suppressor gene (p53) whose inactivation cooperates with Hedgehog pathway for medulloblastoma formation, suggests that 17p deletion unveils haploinsufficiency conditions leading to abrogation of either direct and indirect checkpoints of Hedgehog signalling in cancer.

Cerebellar Neoplasms↗
PubMed2000

Mammary gland tumors in captive African hedgehogs.

From December 1995 to July 1999, eight mammary gland tumors were diagnosed in eight adult captive female African hedgehogs (Atelerix albiventris). The tumors presented as single or multiple subcutaneous masses along the cranial or caudal abdomen that varied in size for each hedgehog. Histologically, seven of eight (88%) mammary gland tumors were malignant. Tumors were classified as solid (4 cases), tubular (2 cases), and papillary (2 cases). Seven tumors had infiltrated into the surrounding stroma and three tumors had histologic evidence of neoplastic vascular invasion. Three hedgehogs had concurrent neoplasms. These are believed to be the first reported cases of mammary gland tumors in African hedgehogs.

Adenocarcinoma↗
PubMed1992

Cytoarchitectonic and quantitative Golgi study of the hedgehog supraoptic nucleus.

A cytoarchitectural study was made of the supraoptic nucleus (SON) of the hedgehog with special attention to the quantitative comparison of its main neuronal types. The main purposes were (1) to relate the characteristics of this nucleus in the hedgehog (a primitive mammalian insectivorous brain) with those in the SONs of more evolutionarily advanced species; (2) to identify quantitatively the dendritic fields of the main neuronal types in the hedgehog SON and to study their synaptic connectivity. From a descriptive standpoint, 3 neuronal types were found with respect to the number of dendritic stems arising from the neuronal soma: bipolar neurons (48%), multipolar neurons (45.5%) and monopolar neurons (6.5%). Within the multipolar type 2 subtypes could be distinguished, taking into account the number of dendritic spines: (a) with few spines (93%) and (b) very spiny (7%). These results indicate that the hedgehog SON is similar to that in other species except for the very spiny neurons, the significance of which is discussed. In order to characterise the main types more satisfactorily (bipolar and multipolars with few spines) we undertook a quantitative Golgi study of their dendritic fields. Although the patterns of the dendritic field are similar in both neuronal types, the differences in the location of their connectivity can reflect functional changes and alterations in relation to the synaptic afferences.

Anatomy, Comparative↗
PubMedDate not supplied

A comparative histochemical mapping of acid phosphatase, 5-nucleotidase and non-specific esterase in the olfactory bulbs of rabbit and hedgehog.

The paper deals with comparative account of the distribution of acid phosphatase 5-nucleotidase and non-specific esterase in the olfactory bulbs of rabbit and hedgehog. The acid phosphatase is observed in all the neurons of both the animals. However, the concentration of the enzyme is higher in hedgehog as compared to rabbit. The intensity of 5-nucleotidase in all the layers of olfactory bulb of hedgehog is stronger than in the rabbit. Intensity of non-specific esterase is quite higher in the olfactory bulb of rabbit than of hedgehog. Along with comparison the distribution of these enzymes have been correlated with their role in the olfactory senses.

Acid Phosphatase↗
PubMed1995

Constancy and variability in cortical structure. A study on synapses and dendritic spines in hedgehog and monkey.

Synapses and dendritic spines were investigated in the parietal cortex of the hedgehog (Erinaceus europaeus) and the monkey (Macaca mulatta). There was no significant difference in the density of synapses between the two species (14 synapses/100 microns2 in the hedgehog, 15/100 microns2 in the monkey), neither in the size of the synaptic junctions, in the proportion of Type I and Type II synapses (8-10% were of Type II in the hedgehog, 10-14% in the monkey) nor in the proportion of perforated synapses (8% in the hedgehog, 5% in the monkey). The only striking difference at the electron microscopic level concerned the frequency of synapses in which the postsynaptic profile was deeply indented into the presynaptic terminal. Such synapses were 10 times more frequent in the monkey. Dendritic spines were investigated in Golgi-preparations. The density of spines along dendrites was similar in both species. The results are discussed with regard to connectivity in the cortex of small and large brains.

Animals↗
PubMed1998

Fatal cryptosporidiosis in a juvenile captive African hedgehog (Ateletrix albiventris).

Fatal intestinal cryptosporidiosis of unknown source and unexplained epizootiology is reported in a neonatal captive African hedgehog (Ateletrinx albiventris) and for the first time in a hedgehog species. The infection, confined to ileum, jejunum, and colon, was extremely severe in the lower jejunum where over 75% of the epithelial cells harbored the pathogen. The ileum and the jejunum displayed moderate and severe villus atrophy and mucosal hyperplasia. Lamina propria and mucosa were infiltrated by eosinophils, lymphocytes, and macrophages. Developmental stages of Cryptosporidium sp. produced a positive reaction with immunofluorescent antibody for detection of the human pathogen, Cryptosporidium parvum. Personnel of captive centers with hedgehogs should be alerted and undertake appropriate precautions to prevent zoonotic transmission. Commercially offered hedgehog-pets may pose a risk for Cryptosporidium infection for human immunodeficiency virus-infected people.

Animals↗
PubMed2001

No evidence of deregulated patched-hedgehog signaling pathway in trichoblastomas and other tumors arising within nevus sebaceous.

Nevus sebaceous is a congenital malformation of the skin within which a number of neoplasms showing adnexal differentiation may arise. Recently, deletions in the patched gene region were reported in nevus sebaceous and constitutive activation of the patched-hedgehog signaling pathway was implicated in the development of tumors arising within nevus sebaceous. To substantiate further a role of the patched-hedgehog signaling pathway in secondary tumors arising within nevus sebaceous, we examined 11 nevus sebaceous associated with secondary tumors for loss of heterozygosity of the patched gene region by microsatellite polymerase chain reaction and patched mRNA expression by in situ hybridization. Unexpectedly, however, none of the tumors (including eight trichoblastomas) and nevus sebaceous lesions showed loss of heterozygosity at any polymorphic loci close to the patched gene. Further more, none of the nevus sebaceous lesions and secondary tumors gave detectable signals for patched mRNA. In contrast, four of 11 sporadic basal cell carcinomas, that were examined for comparison, showed loss of heterozygosity at the patched gene locus (p <0.05), and moderate to strong signals for patched mRNA was observed in all seven basal cell carcinoma tumors examined (p <0.0001). Additional investigation by reverse transcription-polymerase chain reaction in four basal cell carcinomas and two nevus sebaceous tumors also showed the expression of Gli-1, another target gene in the patched-hedgehog signaling pathway, in all the basal cell carcinomas samples but not in any of the nevus sebaceous tumors examined. The findings in this study do not support the view that the deregulation of the patched-hedgehog signaling pathway is involved in the pathogenesis of nevus sebaceous and associated tumors, and show that, although morphologically similar, trichoblastomas and basal cell carcinomas have a different molecular pathogenesis.

Adult↗
PubMed2004

Immunoprevention of basal cell carcinomas with recombinant hedgehog-interacting protein.

Basal cell carcinomas (BCCs) are driven by abnormal hedgehog signaling and highly overexpress several hedgehog target genes. We report here our use of one of these target genes, hedgehog-interacting protein (Hip1), as a tumor-associated antigen for immunoprevention of BCCs in Ptch1+/- mice treated with ionizing radiation. Hip1 mRNA is expressed in adult mouse tissues at levels considerably lower than those in BCCs. Immunization with either of two large recombinant Hip1 polypeptides was well tolerated in Ptch1+/- mice, induced B and T cell responses detectable by enzyme-linked immunosorbent assay, Western blot, delayed type hypersensitivity, and enzyme-linked immunospot assay, and reduced the number of BCCs by 42% (P < 0.001) and 32% (P < 0.01), respectively. We conclude that immunization with proteins specifically up-regulated by hedgehog signaling may hold promise as a preventive option for patients such as those with the basal cell nevus syndrome who are destined to develop large numbers of BCCs.

Animals↗