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PubMed1985

The coexistence of oxytocin and corticotropin-releasing factor in the hypothalamus: an immunocytochemical study in the rat, sheep and hedgehog.

The unlabeled antibody enzyme method has been applied on adjacent sections in order to investigate coexistence of oxytocin (OXY) and corticotropin-releasing factor (CRF) within individual neurons of the hypothalamic paraventricular nucleus of the colchicine-treated rat, sheep and hedgehog. Our results show that, although OXY and CRF immunoreactivities are both expressed by a number of cells in the rat and the sheep paraventricular nucleus, this is not the case for the hedgehog.

Animals↗
PubMed1989

Vasoactive intestinal polypeptide-immunoreactive neurons in the main olfactory bulb of the hedgehog (Erinaceus europaeus).

Vasoactive intestinal polypeptide (VIP) immunoreactivity was localized by the indirect antibody enzyme method (PAP technique) in the main olfactory bulb of the hedgehog. Most VIP-immunoreactive cells were located in the glomerular layer and throughout the external plexiform layer. Fewer cells were observed in the granule cell layer. At the morphological level they exhibit the characteristics of periglomerular, external tufted, superficial short axon, horizontal and Van Gehuchten cells. It should be mentioned that another specific neuronal type was found in the inner third of the external plexiform layer, which is not described in other animals. These results revealed that a high number of intrinsic neuronal types of the olfactory bulb of the hedgehog display a strong VIP immunoreactivity.

Animals↗
PubMed1995

Induction of midbrain dopaminergic neurons by Sonic hedgehog.

Midbrain dopaminergic neurons, whose loss in adults results in Parkinson's disease, can be specified during embryonic development by a contact-dependent signal from floor plate cells. Here we show that the amino-terminal product of Sonic hedgehog autoproteolysis (SHH-N), an inductive signal expressed by floor plate cells, can induce dopaminergic neurons in vitro. We show further that manipulations to increase the activity of cyclic AMP-dependent protein kinase A, which is known to antagonize hedgehog signaling, can block dopaminergic neuron induction by floor plate cells. Our results and those of other studies indicate that SHH-N can function in a dose-dependent manner to induce different cell types within the neural tube. Our results also provide the basis for a potential cell transplantation therapy for Parkinson's disease.

Animals↗
PubMed1995

Signalling by hedgehog family proteins in Drosophila and vertebrate development.

Members of the hedgehog gene family encode a novel class of secreted proteins and are expressed in embryonic cells known to possess important signalling activities in organisms as diverse as flies and chickens. Proteins of the hedgehog family act in these different developmental contexts as both permissive and instructive signals. How this signalling activity is transduced is (as yet) poorly understood, but recent studies point to the involvement of protein kinase A in both Drosophila and vertebrates.

Animals↗
PubMed2006

Hedgehog peptide promotes cell polarization and lumen formation in developing mouse submandibular gland.

Tube formation of the developing mouse submandibular salivary gland (SMG) begins at embryonic day (E) 14. The SMG of Sonic hedgehog (Shh) null mice was recently shown to fail to progress to stages beyond around E14. Here, we examined the effects of Shh peptide on tube formation of SMG explants. When the SMG rudiments from E14 mice were cultured, terminal buds of glands treated with Shh peptide formed the acini-like structure with a lumen whereas those of control glands remained as cell masses. In the acini-like terminal buds of the treated glands, tight junction proteins of ZO-1 and claudin-3 delineated the lumen and the apical membrane protein aquaporin-5 accumulated at the luminal cell surfaces. Moreover, laminin-5 deposition at the basal lamina region of terminal buds was accelerated in treated glands. It is suggested that hedgehog signaling promotes lumen formation and cell polarization of developing SMG epithelium.

Animals↗
PubMed2006

Sonic hedgehog stimulates the proliferation of rat gastric mucosal cells through ERK activation by elevating intracellular calcium concentration.

Sonic Hedgehog (Shh), a member of hedgehog peptides family, is expressed in gastric gland epithelium. To elucidate Shh function to gastric mucosal cells, we examined the effect of Shh on the proliferation of a rat normal gastric mucosal cell line, RGM-1. RGM-1 cells express essential components of Shh receptor system, patched-1, and smoothened. Shh enhanced DNA synthesis in RGM-1 cells and elevated intracellular calcium concentration ([Ca2+]i). In addition, Shh as well as calcium ionophore A32187 rapidly activated ERK. However, Shh failed to activate ERK under calcium-free culture condition. Pretreatment of cells with PD98059 attenuated the DNA synthesis promoted by Shh. Moreover, when cells were pretreated with cyclopamine, Shh could not elevate [Ca2+]i, activate ERK or promote DNA synthesis. On the other hand, although Shh induced Gli-1 nuclear accumulation in RGM-1 cells, Shh activated ERK even in cells pretreated with actinomycin D. These results indicate that Shh promotes the proliferation of RGM-1 cells through an intracellular calcium- and ERK-dependent but transcription-independent pathway via Patched/Smoothened receptor system.

Animals↗
PubMed2004

Regulation of Hedgehog signaling: a complex story.

The Hedgehog (Hh) signal transduction pathway plays critical instructional roles during development. Activating mutations in human Hh signaling components predispose to a variety of tumor types, and have been observed in sporadic tumors occurring in a wide range of organs. Multiple insights into the regulation of Hh signaling have been achieved through studies using Drosophila melanogaster as a model organism. In Drosophila, regulation of the transcription factor Cubitus interruptus (Ci) is the ultimate target of the Hh pathway. Ci is regulated through communication of the membrane proteins Patched (Ptc) and Smoothened (Smo) to the intracellular Hedgehog Signaling Complex (HSC) in response to a graded concentration of Hh ligand. The HSC consists of the Kinesin Related Protein, Costal2 (Cos2), the serine-threonine protein kinase. Fused (Fu) and Ci. In the absence of Hh stimulation, the HSC is involved in processing of Ci to a truncated repressor protein. In response to Hh binding to Ptc, processing of Ci is blocked to allow for accumulation of full-length Ci activator protein(s). Differential concentrations of Hh ligand stimulate production of Ci transcriptional activators of varying strength, which facilitate activation of distinct subsets of target genes. The mechanism(s) by which Ptc and Smo communicate with the HSC in response to differential ligand concentrations to regulate Ci function are not yet fully elucidated. Here, we review what is known about regulation of individual Hh signaling components, concentrating on the mechanisms by which the Hh signal is propagated through Smo to the HSC.

Animals↗
PubMed2004

Hedgehog signalling in foregut malignancy.

Hedgehog (Hh) signalling mediates axial patterning and stem cell fate in development. This is mediated by Sonic, Desert and Indian Hedgehogs whose morphogen gradients determine the level of signalling in recipient tissues. Aberrant, cell autonomous, ligand-dependent Hh signalling has recently been demonstrated in small cell lung cancer (SCLC), as well as in upper gastrointestinal malignancies arising from pancreas, esophagus and stomach. These tumors lack mutations in the Hh receptor PATCHED, identifying a mechanism of pathway activation distinct from Gorlin's syndrome associated neural and skin tumors. We believe that this phenomenon represents a conserved mechanism for establishing niche-independent stem cell fates in cancer which is essential for malignant transformation and metastasis. Specific inhibition of Hh signalling by the naturally occurring plant alkaloid cyclopamine provides the opportunity for pharmacologic assessment of the role of Hh signalling in these tumors. Cyclopamine inhibits growth of SCLC and a wide range of foregut derived malignancies both in vitro and in vivo. This demonstrates an ongoing requirement for Hh signalling in these highly lethal and aggressive tumors. A novel therapeutic strategy is proposed using pharmacologic targeting of Hh dependent tumors with high potency pathway antagonists.

Animals↗
PubMed2006

The ihog cell-surface proteins bind Hedgehog and mediate pathway activation.

The ihog gene (interference hedgehog), identified by RNA interference in Drosophila cultured cells, encodes a type 1 membrane protein shown here to bind and to mediate response to the active Hedgehog (Hh) protein signal. ihog mutations produce defects characteristic of Hh signaling loss in embryos and imaginal discs, and epistasis analysis places ihog action at or upstream of the negatively acting receptor component, Patched (Ptc). The first of two extracellular fibronectin type III (FNIII) domains of the Ihog protein mediates a specific interaction with Hh protein in vitro, but the second FNIII domain is additionally required for in vivo signaling activity and for Ihog-enhanced binding of Hh protein to cells coexpressing Ptc. Other members of the Ihog family, including Drosophila Boi and mammalian CDO and BOC, also interact with Hh ligands via a specific FNIII domain, thus identifying an evolutionarily conserved family of membrane proteins that function in Hh signal response.

Animals↗
PubMed2004

Purmorphamine induces osteogenesis by activation of the hedgehog signaling pathway.

Previously, a small molecule, purmorphamine, was identified that selectively induces osteogenesis in multipotent mesenchymal progenitor cells. In order to gain insights into the mechanism of action of purmorphamine, high-density oligonucleotide microarrays were used to profile gene expression in multipotent mesenchymal progenitor cells treated with either purmorphamine or bone morphogenetic protein-4 (BMP-4). In contrast to BMP-4 treatment, purmorphamine activates the Hedgehog (Hh) signaling pathway, resulting in the up- and downregulation of its downstream target genes, including Gli1 and Patched. Moreover, the known Hh signaling antagonists, cyclopamine and forskolin, completely block the osteogenesis and Glimediated transcription induced by purmorphamine. These results demonstrate that purmorphamine is a small molecule agonist of Hedgehog signaling, and it may ultimately be useful in the treatment of bone-related disease and neurodegenerative disease.

Alkaline Phosphatase↗
PubMed2004

Hedgehog signaling: iguana debuts as a nuclear gatekeeper.

The intracellular pathway that controls the cytoplasmic versus nuclear distribution of Gli transcriptional regulators in response to Hedgehog signaling remains poorly understood. Iguana appears to play a role in regulating this process independently of Hedgehog signaling.

Animals↗
PubMed2007

Cytologic diagnosis of diseases of hedgehogs.

This article focuses on neoplastic diseases because they may be the most frequent disease processes in captive hedgehogs according to the literature and authors' case files and the most common cases submitted for cytologic diagnosis in these species, particularly the African hedgehog (Atelerix albiventris).

Animals↗
PubMed2005

Shifted, the Drosophila ortholog of Wnt inhibitory factor-1, controls the distribution and movement of Hedgehog.

We here identify and characterize an extracellular modulator of Hedgehog signaling in Drosophila, Shifted. Shifted is required for high levels of long-range signaling in the developing wing imaginal disc. Surprisingly, shifted encodes the only Drosophila ortholog of the secreted vertebrate protein Wnt Inhibitory Factor-1 (WIF-1), whose known role is to bind to extracellular Wnts and inhibit their activity. However, Shifted does not regulate Hedgehog signaling by affecting Wingless or Wnt signaling. We show instead that Shifted is a secreted protein that acts over a long distance and is required for the normal accumulation of Hh protein and its movement in the wing. Our data further indicate that Shf interacts with Hh and the heparan sulfate proteoglycans. Therefore, we propose that Shf stabilizes the interaction between Hh and the proteoglycans, an unexpected role for a member of the WIF-1 family.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Costal-2: a scaffold for kinases mediates Hedgehog signaling.

Drosophila genetics has identified several components of the Hedgehog signaling pathway, but the mechanism by which they act remains elusive. In this issue of Developmental Cell, a report by Zhang et al. provides evidence that the kinesin-related protein Costal-2 forms a multi-component scaffold that mediates Hedgehog signaling.

Animals↗
PubMed2006

The cell surface membrane proteins Cdo and Boc are components and targets of the Hedgehog signaling pathway and feedback network in mice.

Cdo and Boc encode cell surface Ig/fibronectin superfamily members linked to muscle differentiation. Data here indicate they are also targets and signaling components of the Sonic hedgehog (Shh) pathway. Although Cdo and Boc are generally negatively regulated by Hedgehog (HH) signaling, in the neural tube Cdo is expressed within the Shh-dependent floor plate while Boc expression lies within the dorsal limit of Shh signaling. Loss of Cdo results in a Shh dosage-dependent reduction of the floor plate. In contrast, ectopic expression of Boc or Cdo results in a Shh-dependent, cell autonomous promotion of ventral cell fates and a non-cell-autonomous ventral expansion of dorsal cell identities consistent with Shh sequestration. Cdo and Boc bind Shh through a high-affinity interaction with a specific fibronectin repeat that is essential for activity. We propose a model where Cdo and Boc enhance Shh signaling within its target field.

Animals↗
PubMed2006

Hedgehog signaling in small-cell lung cancer: frequent in vivo but a rare event in vitro.

The hedgehog (HH) signaling pathway plays multiple roles during embryonic development and increasing evidence suggests that this embryonic pathway is involved in development and progression of several human cancers including those of the brain, skin, lung and gastrointestinal tract. To investigate HH signaling activity in small-cell lung cancer (SCLC), we have performed gene expression analysis on members of the HH pathway on a panel of 20 SCLC cell lines. Sonic hedgehog (SHH) expression was detected in only DMS79 and GLC16 and only DMS114 expressed detectable protein levels of GLI1, one of the key transcription factors of the pathway. Involvement of HH signaling in SCLC proliferation was investigated in a subset of cell lines using the HH signaling inhibitor cyclopamine or small interfering RNA (siRNA) against GLI1. Cells expressing GLI1 responded only weakly to both cyclopamine and RNA interference, suggesting that HH signaling plays only a minor role in the growth of SCLC cell lines. To investigate HH pathway activity in vivo, GLI1 immunohistochemistry was performed on SCLC tumors. Interestingly, GLI1 was expressed in most SCLC tumors studied, indicating that HH signaling is important for in vivo growth of SCLC but establishment of cell lines from SCLC tumors may lead to loss of expression of key HH pathway members. Thus, the data support the idea that the HH pathway may be a therapeutic target in SCLC. However, the data also suggest that the SCLC cells can circumvent the apparent in vivo requirement of HH signaling.

Carcinoma, Small Cell↗
PubMed2006

Direct and indirect effects of hedgehog pathway activation in the mammalian retina.

The morphogen Sonic hedgehog (Shh) is expressed by the projection neurons of the retina, retinal ganglion cells (RGCs) and promotes retinal precursor cell (RPC) proliferation. To distinguish between direct and indirect effects of Hedgehog (Hh) pathway activation in the perinatal mouse retina, we followed the fate of cells that expressed a constitutively active allele of Smoothened (SMO-M2), the signal transduction component of the Hh pathway. SMO-M2 expression promoted a cell-autonomous increase in CyclinD1 expression and RPC proliferation and promoted the development of cells with an inner nuclear layer identity. SMO-M2 expression also inhibited rhodopsin expression in uninfected cells, thus highlighting an unexpected non-cell autonomous effect of Hh pathway activation on photoreceptor development.

Animals↗
PubMed2005

Hedgehog and retinoid signalling confines nkx2.2b expression to the lateral floor plate of the zebrafish trunk.

The ventral neural tube of vertebrates consists of distinct neural progenitor domains positioned along the dorsoventral (DV) axis that develop different types of moto- and interneurons. Several signalling molecules, most notably Sonic Hedgehog (Shh), retinoic acid (RA) and fibroblast growth factor (FGF) have been implicated in the generation of these domains. Shh is secreted from the floor plate, the ventral most neural tube structure that consists of the medial (MFP) and the lateral floor plate (LFP). While the MFP is well characterized, organization and function of the LFP remains unclear. Here, we describe the novel homeobox gene nkx2.2b that is strongly expressed in the trunk LFP of zebrafish and thus represents a unique marker for the characterization of LFP formation and the identification of LFP deficient mutants. nkx2.2b and its paralog nkx2.2a (formerly known as nk2.2 and nkx2.2) arose by gene duplication in zebrafish. Both duplicates show significant differences in their expression patterns. For example, while prominent nkx2.2a expression has been described in the ventral brain [Barth, K.A., Wilson, S.W., 1995. Expression of zebrafish nk2.2 is influenced by sonic hedgehog/vertebrate hedgehog-1 and demarcates a zone of neuronal differentiation in the embryonic forebrain. Development 121, 1755-1768], hardly any expression can be found in the trunk LFP, which is in contrast to nkx2.2b. Overexpression, mutant and inhibitor analyses show that nkx2.2b expression in the LFP is up-regulated by Shh, but repressed by retinoids and ectopic islet-1 (isl1) expression. In contrast to previously described zebrafish trunk LFP markers, like e.g. tal2 or foxa2, nkx2.2b is exclusively expressed in the LFP. Thus, it represents a unique tool to analyse the mechanisms of ventral neural tube patterning in zebrafish.

Amino Acid Sequence↗