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PubMed2001

Hedgehog signaling is required for primary motoneuron induction in zebrafish.

Sonic hedgehog (Shh) is crucial for motoneuron development in chick and mouse. However, zebrafish embryos homozygous for a deletion of the shh locus have normal numbers of motoneurons, raising the possibility that zebrafish motoneurons may be specified differently. Unlike other vertebrates, zebrafish express three hh genes in the embryonic midline: shh, echidna hedgehog (ehh) and tiggywinkle hedgehog (twhh). Therefore, it is possible that Twhh and Ehh are sufficient for motoneuron formation in the absence of Shh. To test this hypothesis we have eliminated, or severely reduced, all three Hh signals using mutations that directly or indirectly reduce Hh signaling and antisense morpholinos. Our analysis shows that Hh signals are required for zebrafish motoneuron induction. However, each of the three zebrafish Hhs is individually dispensable for motoneuron development because the other two can compensate for its loss. Our results also suggest that Twhh and Shh are more important for motoneuron development than Ehh.

Animals↗
PubMed2002

Distinct and cooperative roles for Nodal and Hedgehog signals during hypothalamic development.

Despite its evolutionary conservation and functional importance, little is known of the signaling pathways that underlie development of the hypothalamus. Although mutations affecting Nodal and Hedgehog signaling disrupt hypothalamic development, the time and site of action and the exact roles of these pathways remain very poorly understood. Unexpectedly, we show here that cell-autonomous reception of Nodal signals is neither required for the migration of hypothalamic precursors within the neural plate, nor for further development of the anterior-dorsal hypothalamus. Nodal signaling is, however, cell-autonomously required for establishment of the posterior-ventral hypothalamus. Conversely, Hedgehog signaling antagonizes the development of posterior-ventral hypothalamus, while promoting anterior-dorsal hypothalamic fates. Besides their distinct roles in the regionalization of the diencephalon, we reveal cooperation between Nodal and Hedgehog pathways in the maintenance of the anterior-dorsal hypothalamus. Finally we show that it is the prechordal plate and not the head endoderm that provides the early signals essential for establishment of the hypothalamus.

Animals↗
PubMed2002

Hedgehog is required for murine yolk sac angiogenesis.

Blood islands, the precursors of yolk sac blood vessels, contain primitive erythrocytes surrounded by a layer of endothelial cells. These structures differentiate from extra-embryonic mesodermal cells that underlie the visceral endoderm. Our previous studies have shown that Indian hedgehog (Ihh) is expressed in the visceral endoderm both in the visceral yolk sac in vivo and in embryonic stem (ES) cell-derived embryoid bodies. Differentiating embryoid bodies form blood islands, providing an in vitro model for studying vasculogenesis and hematopoiesis. A role for Ihh in yolk sac function is suggested by the observation that roughly 50% of Ihh(-/-) mice die at mid-gestation, potentially owing to vascular defects in the yolk sac. To address the nature of the possible vascular defects, we have examined the ability of ES cells deficient for Ihh or smoothened (Smo), which encodes a receptor component essential for all hedgehog signaling, to form blood islands in vitro. Embryoid bodies derived from these cell lines are unable to form blood islands, and express reduced levels of both PECAM1, an endothelial cell marker, and alpha-SMA, a vascular smooth muscle marker. RT-PCR analysis in the Ihh(-/-) lines shows a substantial decrease in the expression of Flk1 and Tal1, markers for the hemangioblast, the precursor of both blood and endothelial cells, as well as Flt1, an angiogenesis marker. To extend these observations, we have examined the phenotypes of embryo yolk sacs deficient for Ihh or SMO: Whereas Ihh(-/-) yolk sacs can form blood vessels, the vessels are fewer in number and smaller, perhaps owing to their inability to undergo vascular remodeling. Smo(-/-) yolk sacs arrest at an earlier stage: the endothelial tubes are packed with hematopoietic cells, and fail to undergo even the limited vascular remodeling observed in the Ihh(-/-) yolk sacs. Our study supports a role for hedgehog signaling in yolk sac angiogenesis.

Animals↗
PubMed2002

Hedgehogs tryst with the cell cycle.

Hedgehog proteins play an essential role during pattern formation in animal development and, increasingly, much of our appreciation of their modes of action is emanating from studies of their signalling mechanisms at the cellular level. Recent work has provided insights into how Hedgehog controls the cell cycle in a variety of circumstances. The data suggest that this influence may be direct and operates through interaction of the signalling pathway with cell cycle regulators at multiple points within the cell cycle. These new findings have profound implications in the context of clinical conditions - especially cancers - that arise from de-regulated cell proliferation in response to aberrant Hedgehog signalling activity.

Animals↗
PubMed2005

Hedgehog antagonist REN(KCTD11) regulates proliferation and apoptosis of developing granule cell progenitors.

During the early development of the cerebellum, a burst of granule cell progenitor (GCP) proliferation occurs in the outer external granule layer (EGL), which is sustained mainly by Purkinje cell-derived Sonic Hedgehog (Shh). Shh response is interrupted once GCPs move into the inner EGL, where granule progenitors withdraw proliferation and start differentiating and migrating toward the internal granule layer (IGL). Failure to interrupt Shh signals results in uncoordinated proliferation and differentiation of GCPs and eventually leads to malignancy (i.e., medulloblastoma). The Shh inhibitory mechanisms that are responsible for GCP growth arrest and differentiation remain unclear. Here we report that REN, a putative tumor suppressor frequently deleted in human medulloblastoma, is expressed to a higher extent in nonproliferating inner EGL and IGL granule cells than in highly proliferating outer EGL cells. Accordingly, upregulated REN expression occurs along GCP differentiation in vitro, and, in turn, REN overexpression promotes growth arrest and increases the proportion of p27/Kip1+ GCPs. REN also impairs both Gli2-dependent gene transcription and Shh-enhanced expression of the target Gli1 mRNA, thus antagonizing the Shh-induced effects on the proliferation and differentiation of cultured GCPs. Conversely, REN functional knock-down impairs Hedgehog antagonism and differentiation and sustains the proliferation of GCPs. Finally, REN enhances caspase-3 activation and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling apoptotic GCP numbers; therefore, the pattern of REN expression, its activity, and its antagonism on the Hedgehog pathway suggest that this gene may represent a restraint of Shh signaling at the outer to inner EGL GCP transitions. Medulloblastoma-associated REN loss of function might withdraw such a limiting signal for immature cell expansion, thus favoring tumorigenesis.

Animals↗
PubMed1987

Relationship between body and testis temperatures in the European hedgehog, Erinaceus europaeus, during hibernation and sexual reactivation.

Simultaneous telemetry of the body and testis temperatures of 8 hedgehogs was carried out during hibernation and during sexual reactivation in spring. Between October and January, when the testes were involuted, the body/testis temperature differential was variable, with mean daily testis temperatures up to 1 degrees C warmer than body temperatures. From mid-February onwards, when plasma testosterone approached maximal concentrations, mean testicular temperatures stabilized 1.4 +/- 0.2 degrees C below body temperatures. During spermatogenesis testicular temperature of hedgehogs was significantly lower than body temperature. Over the euthermic body temperature range of 34.7-36.2 degrees C, testicular temperatures varied from 34.0 to 34.9 degrees C. Only at body temperatures over 36.2 degrees C did testicular temperature reach 35 degrees C. During spermatogenesis hedgehog testis temperatures are similar to those of many scrotal mammals.

Animals↗
PubMed1989

Daily and seasonal variations in plasma LH and testosterone concentrations in the adult male hedgehog (Erinaceus europaeus).

A double-antibody heterologous radioimmunoassay (RIA) was developed to measure plasma LH values in hedgehogs. This RIA system used anti-rat LH serum and rabbit LH (AFP-559B) for radioiodination and as standard. The accuracy of the method was evaluated and indicated the ability to detect various relative concentrations of LH in plasma. The minimum detectable dose was 0.2 ng/ml. The intra- and inter-assay coefficients of variation were 4.2 and 7.9% respectively. Biological tests, e.g. effect of castration, effect of castration + testosterone implant and GnRH administration, confirmed that this method was suitable to determine subsequent changes in pituitary gonadotrophic activity in the hedgehog. LH concentrations were determined in blood samples obtained during 1 year: (a) each month, at 4-h intervals during 24 h, from different groups of unanaesthetized animals fitted with a catheter and (b) twice a month, under a light anaesthesia, from the same group of 6 animals. During the year: (1) the range of LH change was narrow (minimum values congruent to 0.25 ng/ml and maximum values congruent to 2.00 ng/ml); (2) the 24-h LH patterns did not exhibit any daily rhythm; (3) a clear annual rhythm was observed with the highest values from February to April and the lowest values in October and November. LH decreased rapidly at the end of summer and increased progressively from December to February, during hibernation. In these experiments, it was not possible to determine the characteristics of LH release patterns in the hedgehog but individual profiles indicated clearly the episodic secretion of LH, particularly during the highest pituitary activity period. During the year, a close relationship between the seasonal cycles of plasma LH and testosterone was observed.

Animals↗
PubMed2000

Reproductive characteristics of the african pygmy hedgehog, atelerix albiventris.

To obtain further perspective on reproduction and particularly gamete function among so-called primitive mammals presently grouped in the Order Insectivora, we have examined the African hedgehog, Atelerix albiventris, in light of unusual features reported in shrews and moles. Atelerix proves to share many but not all of the characteristics seen in these other insectivores. The penis of Atelerix has a 'snail-like' form, but lacks the surface spines common in insectivores and a number of other mammals. Hedgehog spermatozoa display an eccentric insertion of the tail on the sperm head, and they manifest the barbs on the perforatorium that, in shrews, probably effect the initial binding of the sperm head to the zona pellucida. As a possible correlate, the structural matrix of the hedgehog acrosome comprises only two main components, as judged by immunoblotting, rather than the complex of peptides seen in the matrix of some higher mammals. The Fallopian tube of Atelerix is relatively simple; it displays only minor differences in width and in the arborized epithelium between the isthmus and ampulla, and shows no evidence of the unusual sperm crypts that characterize the isthmus or ampulla, depending on the species, in shrews and moles. In common with other insectivores, Atelerix appears to be an induced ovulator, as judged by the ovulation of some 6-8 eggs by about 23 h after injection of hCG. The dense cumulus oophorus appeared to have little matrix, in keeping with the modest dimensions of the tubal ampulla and, while it was not quite as discrete as that of soricids, it did show the same insensitivity to 0.5% (w/v) ovine or bovine hyaluronidase.

Acrosome↗
PubMed1980

Structural and functional characteristics of hedgehog polysensory cortical zone.

The study of the neuronal organization of the hedgehog associative cortical zone revealed that besides primitive characteristics this area possesses a number of progressive features. An electrophysiological approach revealed a great number of polysensory neurons. The method, based on the HRP retrograde axonal transport, enabled us to discover the connections between primitive associative LP and MD thalamic nuclei and the associative cortex. Motor conditioned reflexes connected with visual discrimination as well as reflexes to signals of different modalities were elaborated quite easily. Conditioning to a simultaneous visual-auditory complex was found impossible in hedgehogs. Bilateral ablation of associative area results in disruption of the fine components of sensorimotor integration. It is likely that a primitively organized associative system in hedgehogs participates in the formation of sensorimotor synthesis, but fails to realize complex acts of intersensory integration.

Animals↗
PubMed2005

Hedgehog zoonoses.

Exotic pets, including hedgehogs, have become popular in recent years among pet owners, especially in North America. Such animals can carry and introduce zoonotic agents, a fact well illustrated by the recent outbreak of monkeypox in pet prairie dogs. We reviewed known and potential zoonotic diseases that could be carried and transmitted by pet hedgehogs or by wild-caught hedgehogs that have been rescued.

Animals↗
PubMed2006

Expressions of sonic hedgehog, patched, smoothened and Gli-1 in human intestinal stromal tumors and their correlation with prognosis.

AIM: To investigate the role that the hedgehog (Hh) signaling pathway, which includes sonic hedgehog (Shh), Patched (Ptc), Smoothened (Smo) and Gli-1, plays in human gastrointestinal stromal tumors (GISTs). METHODS: Surgically resected specimens from patients with GISTs, leiomyomas and schwannomas were examined by immunohistochemical staining for aberrant expression of hedgehog signaling components, Shh, Ptc, Smo and Gli-1, respectively. RESULTS: In GISTs, 58.1% (18 of 31), 77.4% (24 of 31), 80.6% (25 of 31) and 58.1% (18 of 31) of the specimens stained positive for Shh, Ptc, Smo and Gli-1, respectively. In leiomyomas, 92.3% (12 of 13), 92.3% (12 of 13), 69.2% (9 of 13) and 92.3% (12 of 13) stained positive for Shh, Ptc, Smo and Gli-1, respectively. In schwannomas, 83.3% (5 of 6), 83.3% (5 of 6), 83.3% (5 of 6) and 100% (6 of 6) stained positive for Shh, Ptc, Smo and Gli-1, respectively. Immunohistochemistry revealed that the expressions of Shh and Gli-1 were significantly higher in leiomyomas than in GISTs (P < 0.05, respectively). Shh expression strongly correlated with the grade of tumor risk category and with tumor size (P < 0.05, respectively). However, the expressions of Ptc and Smo did not correlate with histopathological differentiation. CONCLUSION: These results suggest that the Hh signaling pathway may play an important role in myogenic differentiation and the malignant potential of human intestinal stromal tumors.

Cell Transformation, Neoplastic↗
PubMed1998

Intestinal lymphosarcoma in captive African hedgehogs.

Two captive adult female African hedgehogs (Atelerix albiventris) had inappetance and bloody diarrhea for several days prior to death. Both hedgehogs had ulceration of the small intestine and hepatic lipidosis. Histopathology revealed small intestinal lymphosarcoma with metastasis to the liver. Extracellular particles that had characteristics of retroviruses were observed associated with the surface of some neoplastic lymphoid cells by transmission electron microscopy. These are the first reported cases of intestinal lymphosarcoma in African hedgehogs.

Animals↗
PubMed1999

Schwann cell-derived desert hedgehog signals nerve sheath formation.

Reciprocal signaling between axons and Schwann cells during development is well established. The contribution of Schwann cells to the formation and maintenance of the protective nerve sheaths (endo-, peri-, and epineurium) has been less studied. Although mesenchymal cells contribute to all these structures, only perineurial cells contribute to the diffusion barrier between nerves and surrounding tissues. During development, prospective perineurial cells shift from a mesenchymal to epithelial phenotype, forming concentric layers of cells around the nerve fascicles that collectively form a barrier against unwanted molecules and cellular infiltration. We have studied the role of Schwann cells in the formation and maintenance of this barrier. The signaling molecule Desert hedgehog is expressed in Schwann cell precursors, and in Schwann cells until at least postnatal day 10, while its receptor patched is seen in mesenchymal cells surrounding the developing nerve at embryo day 15. In Desert hedgehog knockout mice, the connective tissue sheaths in adult nerves appear highly abnormal by electron microscopy. There is almost no epineurium, and the perineurium is thin and highly abnormal. In addition, perineurial-like cells invade the endoneurial space, forming mini-fascicles around small bundles of nerve fibers similar to those seen in regenerating nerves. Functional tests reveal that the diffusion and cellular infiltration barrier is compromised, demonstrating that Desert hedgehog signaling from Schwann cells to the mesenchyme is involved in the formation of a morphologically and functionally normal perineurium.

Aging↗
PubMed2001

Calretinin-, neurocalcin-, and parvalbumin-immunoreactive elements in the olfactory bulb of the hedgehog (Erinaceus europaeus).

The distribution pattern and morphology of calretinin-, neurocalcin-, and parvalbumin-immunoreactive neurons were studied in the main and accessory olfactory bulbs of the hedgehog. The detection of these markers was carried out by using monoclonal or polyclonal antibodies and the avidin-biotin-immunoperoxidase method. Specific neuronal populations were positive for these calcium-binding proteins in the hedgehog olfactory bulb, revealing both similarities to and differences from the data reported in the olfactory bulb of rodent species. The distribution pattern of each calcium-binding protein studied in the accessory olfactory bulb was highly similar to that described in other macrosmatic species. However, in the main olfactory bulb, the markers analyzed were expressed in similar interneuronal populations as they are in the rodent olfactory bulb, whereas cell groups categorized as projecting neurons demonstrated striking differences in the expression of these calcium-binding proteins. These results suggest that the expression of calcium-binding proteins in a given brain region is not a constant feature among species despite a similar organization but that different factors could influence their expression. Thus, the accessory olfactory system involved in the processing of specific and similar olfactory cues among species demonstrates a more constant organization among species. By contrast, the functionally important role of the main olfactory system in the hedgehog is accompanied by a more complex organization, which is reflected in an increased diversity of calcium-buffering systems.

Animals↗
PubMed2003

Evidence for lack of enhanced hedgehog target gene expression in common extracutaneous tumors.

Abnormal hedgehog signaling, most commonly caused by loss of PTCH1 inhibitor activity,drives tumorigenesis of basal cell carcinomas (BCCs). To assess whether other tumors also have abnormal hedgehog signaling, we have assayed RNA from common cancers at nine different sites for levels of expression of hedgehog target genes that are up-regulated uniformly in BCCs. We report here that such dysregulation appears not to be common in the types of non-BCC cancers studied, indicating that the molecular pathogenesis of BCCs, like their frequency and behavior, differs markedly from that of most other cancers.

Adolescent↗
PubMed1992

Parvalbumin and calbindin immunoreactivity in the cerebral cortex of the hedgehog (Erinaceus europaeus).

To investigate the morphology and distribution of nonpyramidal neurons in the brain of insectivores, parvalbumin and calbindin 28 kDa immunoreactivity was examined in the cerebral cortex of the hedgehog (Erinaceus europaeus). Parvalbumin-immunoreactive cells were found in all layers of the isocortex, but in contrast to other mammals, a laminar organisation or specific regional distribution was not seen. Characteristic parvalbumin-immunoreactive neurons were multipolar cells with large ascending and descending dendrites extending throughout several layers. Calbindin-immunoreactive neurons were similar to those found in other species, although appearing in smaller numbers than in the cerebral cortex of more advanced mammals. The morphology and distribution of parvalbumin- and calbindin-immunoreactive cells in the piriform and entorhinal cortices were similar in hedgehogs and rodents. Parvalbumin-immunoreactive cells in the hippocampal complex were pyramidal-like and bitufted neurons, which were mainly found in the stratum oriens and stratum pyramidale of the hippocampus, and in the stratum moleculare and hilus of the fascia dentata. Heavily stained cells were found in the deep part of the stratum granulare. Intense calbindin immunoreactivity occurred mainly in the granule cell and molecular layers of the dentate gyrus and in the mossy fibre layer. The most outstanding feature in the hippocampal complex of the hedgehog was the extension of calbindin immunoreactivity to CA1 field of the hippocampus, suggesting, in agreement with other reports, that mossy fibres can establish synaptic contacts throughout the pyramidal cell layer.

Animals↗
PubMed1985

Identification and characterization of trypsin, chymotrypsin and elastase inhibitors in the hedgehog, Erinaceus europaeus, and their immunological relationships to those of other mammals (rat, pig and human).

1. Hedgehog plasma was separated by gel filtration on Sephacryl S-200, the fractions resolved by electrophoresis and the electrophoregrams characterized for trypsin, chymotrypsin and elastase inhibiting activities with both low and high molecular weight substrates. Approximate molecular weights were also determined. 2. At least ten protease inhibitors were characterized in hedgehog plasma including three macroglobulins. 3. The hedgehog protease inhibitors were identified by immunoelectrophoresis. Four protease inhibitors showed homologies with specific human, rat or swine antisera. These were alpha 2-and beta-macroglobulins, alpha 1-protease inhibitor, and alpha 2-antithrombin.

Animals↗
PubMed2006

[Expression patterns of sonic hedgehog signaling molecules in human fetal prostate development].

OBJECTIVE: To investigate whether the sonic hedgehog signaling pathway is involved in the development of human fetal prostate, and to evaluate the changing staining patterns of its molecules, sonic hedgehog (SHH), patchedl (PTC1), smoothened (SMO), and GLI1, in the human fetal prostate at various gestation stages. METHODS: Fifteen human fetal prostate specimens at various developmental stages (10 - 39 weeks) were included in this study. SHH, PTC1, SMO and GLI1 were detected in all the specimens by immunohistochemical technique. All the slides were observed and assessed under the light microscope. RESULTS: SHH, PTC1, SMO and GLI1 could be detected in human fetal prostate tissues, and their expression formed two surges, the former at week 16, and the latter at week 28. The staining of SHH and SMO was distributed only in the ductal epithelium but not in the stroma. The expression of PTC1 and GLI1 could be found mainly in the epithelium, with minimal staining in the stroma. CONCLUSION: The sonic hedgehog signaling pathway is involved in the development of the human fetal prostate. The high expression of its molecules at early gestation stages might be associated with the induction of prostatic buds, while their abundant expression at later gestation stages might be related to the prostate ductal branching, growth, differentiation and morphogenesis.

Gene Expression Regulation, Developmental↗