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PubMed1999

Sonic hedgehog signaling by the patched-smoothened receptor complex.

BACKGROUND: The Hedgehog (Hh) family of secreted proteins is involved in a number of developmental processes as well as in cancer. Genetic and biochemical data suggest that the Sonic hedgehog (Shh) receptor is composed of at least two proteins: the tumor suppressor protein Patched (Ptc) and the seven-transmembrane protein Smoothened (Smo). RESULTS: Using a biochemical assay for activation of the transcription factor Gli, a downstream component of the Hh pathway, we show here that Smo functions as the signaling component of the Shh receptor, and that this activity can be blocked by Ptc. The inhibition of Smo by Ptc can be relieved by the addition of Shh. Furthermore, oncogenic forms of Smo are insensitive to Ptc repression in this assay. Mapping of the Smo domains required for binding to Ptc and for signaling revealed that the Smo-Ptc interaction involves mainly the amino terminus of Smo, and that the third intracellular loop and the seventh transmembrane domain are required for signaling. CONCLUSIONS: These data demonstrate that Smo is the signaling component of a multicomponent Hh receptor complex and that Ptc is a ligand-regulated inhibitor of Smo. Different domains of Smo are involved in Ptc binding and activation of a Gli reporter construct. The latter requires the third intracellular loop and the seventh transmembrane domain of Smo, regions often involved in coupling to G proteins. No changes in the levels of cyclic AMP or calcium associated with such pathways could be detected following receptor activation, however.

Amino Acid Sequence↗

PubMed2001

The sonic hedgehog receptor patched associates with caveolin-1 in cholesterol-rich microdomains of the plasma membrane.

The Hedgehog signaling pathway is involved in early embryonic patterning as well as in cancer; however, little is known about the subcellular localization of the Hedgehog receptor complex of Patched and Smoothened. Since Hh has been found in lipid rafts in Drosophila, we hypothesized that Patched and Smoothened might also be found in these cholesterol-rich microdomains. In this study, we demonstrate that both Smoothened and Patched are in caveolin-1-enriched/raft microdomains. Immunoprecipitation studies show that Patched specifically interacts with caveolin-1, whereas Smoothened does not. Fractionation studies show that Patched and caveolin-1 can be co-isolated from buoyant density fractions that represent caveolae/raft microdomains and that Patched and caveolin-1 co-localize by confocal microscopy. Glutathione S-transferase fusion protein experiments show that the interaction between Patched and caveolin-1 involves the caveolin-1 scaffolding domain and a Patched consensus binding site. Immunocytochemistry data and fractionation studies also show that Patched seems to be required for transport of Smoothened to the membrane. Depletion of plasmalemmal cholesterol influences the distribution of the Hh receptor complex in the caveolin-enriched/raft microdomains. These data suggest that caveolin-1 may be integral for sequestering the Hh receptor complex in these caveolin-enriched microdomains, which act as a scaffold for the interactions with the Hh protein.

Amino Acid Sequence↗

PubMed1995

Mycobacterium bovis infection in New Zealand hedgehogs (Erinaceus europaeus).

Seventy-nine wild hedgehogs from the Wairarapa, an area of New Zealand in which bovine tuberculosis is endemic, were examined for lesions suggestive of tuberculosis. Sixteen animals with suspicious lesions had samples submitted for culture. Mycobacterium bovis was recovered from four animals with gross pulmonary lesions. The gross and histopathological appearance of the lesions are described and the significance discussed in the light of previously reported experimental and captive animal infections. It is likely that infection arose from the scavenging behaviour of hedgehogs. The moderate prevalence (5%) of tuberculosis in these animals combined with their small home ranges may allow them to be used in wildlife surveys to pinpoint the locality in which tuberculous possums have died.

Journal Article↗

PubMed2000

The scavenging behaviour of ferrets (Mustela furo), feral cats (Felis domesticus), possums (Trichosurus vulpecula), hedgehogs (Erinaceus europaeus) and harrier hawks (Circus approximans) on pastoral farmland in New Zealand: implications for bovine tuberculosis transmission.

AIMS: To identify species that scavenge carcasses in pastoral habitats in New Zealand; to determine whether there were interspecific or intraspecific differences in scavenging behaviour and; to document any interspecific or intraspecific interactions occurring at carcasses. METHODS: Scavenging by ferrets (Mustela furo), feral cats (Felis domesticus), possums (Trichosurus vulpecula), hedgehogs (Erinaceus europaeus) and harrier hawks (Circus approximans) was studied from autumn to midwinter on pastoral farmland near Palmerston (45S, 170E), Otago, New Zealand. Time-lapse video recorders and camera lens mounted with infra-red light illumination were used to monitor carcasses of 10 ferrets, 12 possums, 2 hedgehogs and 7 rabbits (Oryctolagus cuniculus) until they were totally scavenged. RESULTS: Ferrets scavenged 5/8 ferret carcasses, 8/9 possum carcasses and 6/7 rabbit carcasses encountered. Feral cats scavenged 3/8 ferret carcasses, 5/7 rabbit carcasses, and 3/8 possum carcasses encountered. Possums scavenged 1/2 ferret carcasses and 3/4 rabbit carcasses encountered. The proportion of encounters resulting in feeding on ferret carcasses differed between ferrets (45.7%) and possums (6.3%), and between possums and cats (29.7%). Similarly, for possum carcasses, differences were found between ferrets (76.6%) and possums (0%), ferrets and cats (60.6%) and possums and cats. No interspecific differences were found in the proportion of encounters that resulted in feeding on rabbit carcasses between ferrets (85.2%), possums (75%) and cats (73.1%). In 8/12 instances of ferrets coming into contact with other ferrets whilst feeding, ferrets fed together at the carcass. On 1 occasion, 4 ferrets were recorded feeding together. In 7/8 instances where cats and ferrets came into contact over carrion, ferrets maintained possession or displaced the cat from the carcass. CONCLUSIONS: Communal carrion feeding by ferrets may facilitate intraspecific and interspecific transmission of bovine tuberculosis (caused by Mycobacterium bovis) by the consumption of contaminated carrion, fighting, or close-contact activities. Cannibalism may be one mechanism by which tuberculosis is transmitted within ferret populations. Our results also suggest that possums may acquire infection from carrion, despite being mainly herbivorous.

Journal Article↗

PubMed2000

THE EFFECTS OF 5-AZA-2'-DEOXYCYTIDINE (D-AZA) ON SONIC HEDGEHOG EXPRESSION IN MOUSE EMBRYONIC LIMB BUDS.

5-Aza-2'-deoxycytidine (d-AZA) causes temporally-related defects in the mouse. At 1.0 mg/kg on gestational day (GD) 10, d-AZA causes hindlimb phocomelia. Sonic hedgehog (Shh) plays a significant role in the normal development of limbs in rodent species. Sonic hedgehog peptides, found in the posterior mesenchyme of limb buds, are involved in patterning functions and in the regulation of both anterior-posterior polarity and proximal-distal outgrowth of the limb. The objective of the present study was to analyze alterations in Shh expression subsequent to d-AZA exposure. Pregnant mice were treated with d-AZA via intraperitonlal injection on GD 10. Controls were untreated. The reverse transcription-polymerase chain reaction (RT-PCR), whole mount in situ hybridization (ISH), and whole mount immunohistochemistry (WMI) were used to analyze expression patterns of Shh . For RT-PCR, embryonic hindlimb buds (buds) were taken 0, 4, 8, 12, or 24 hr after exposure. Cyclophilin was used as the baseline monitor. RNA was transcribed to cDNA and used as template with Shh specific primers for amplification. Whole embryos were collected 12 and 24 hr posttreatment for ISH. An antisense primer specific for Shh was used in an oligo-based ISH protocol. Whole embryos were collected 36 and 48 hr posttreatment for WMI. The antibody corresponding to the amino terminal subunit of the Shh peptide was used. There was a treatment related up-regulation of Shh transcripts by 12 and 24 hr posttreatment. The protein response of up-regulation was detectable by 36 and 48 hr posttreatment. Our data suggest that 5-aza-2'-deoxycytidine-induced hindlimb defects may be associated with alterations in the level of Shh expression. This may be part of a cascade of signaling events involved in d-AZA-induced hindlimb defects. Work is ongoing to determine the relationship of other gene species that may cooperate with Shh in the induction of the hindlimb defects.

Journal Article↗

PubMed2005

Receptor tyrosine phosphatase-dependent cytoskeletal remodeling by the hedgehog-responsive gene MIM/BEG4.

During development, dynamic remodeling of the actin cytoskeleton allows the precise placement and morphology of tissues. Morphogens such as Sonic hedgehog (Shh) and local cues such as receptor protein tyrosine phosphatases (RPTPs) mediate this process, but how they regulate the cytoskeleton is poorly understood. We previously identified Basal cell carcinoma-enriched gene 4 (BEG4)/Missing in Metastasis (MIM), a Shh-inducible, Wiskott-Aldrich homology 2 domain-containing protein that potentiates Gli transcription (Callahan, C.A., T. Ofstad, L. Horng, J.K. Wang, H.H. Zhen, P.A. Coulombe, and A.E. Oro. 2004. Genes Dev. 18:2724-2729). Here, we show that endogenous MIM is induced in a patched1-dependent manner and regulates the actin cytoskeleton. MIM functions by bundling F-actin, a process that requires self-association but is independent of G-actin binding. Cytoskeletal remodeling requires an activation domain distinct from sequences required for bundling in vitro. This domain associates with RPTPdelta and, in turn, enhances RPTPdelta membrane localization. MIM-dependent cytoskeletal changes can be inhibited using a soluble RPTPdelta-D2 domain. Our data suggest that the hedgehog-responsive gene MIM cooperates with RPTP to induce cytoskeletal changes.

Actins↗

PubMed2004

Growth and pattern of the mammalian neural tube are governed by partially overlapping feedback activities of the hedgehog antagonists patched 1 and Hhip1.

Upregulation of Patched (Ptc), the Drosophila Hedgehog (Hh) receptor in response to Hh signaling limits the range of signaling within a target field by sequestering Hh. In vertebrates, Ptch1 also exhibits ligand-dependent transcriptional activation, but mutants lacking this response show surprisingly normal early development. The identification of Hh-interacting protein 1 (Hhip1), a vertebrate-specific feedback antagonist of Hh signaling, raises the possibility of overlapping feedback controls. We addressed the significance of feedback systems in sonic hedgehog (Shh)-dependent spinal cord patterning. Mouse embryos lacking both Ptch1 and Hhip1 feedback activities exhibit severe patterning defects consistent with an increased magnitude and range of Hh signaling, and disrupted growth control. Thus, Ptc/Ptch1-dependent feedback control of Hh morphogens is conserved between flies and mice, but this role is shared in vertebrates with Hhip1. Furthermore, this feedback mechanism is crucial in generating a neural tube that contains appropriate numbers of all ventral and intermediate neuronal cell types.

Animals↗

PubMed1997

Smoothened-mediated Hedgehog signalling is required for the maintenance of the anterior-posterior lineage restriction in the developing wing of Drosophila.

It is thought that the posterior expression of the 'selector' genes engrailed and invected control the subdivision of the growing wing imaginal disc of Drosophila into anterior and posterior lineage compartments. At present, the cellular mechanisms by which separate lineage compartments are maintained are not known. Most models have assumed that the presence or absence of selector gene expression autonomously drives the expression of compartment-specific adhesion or recognition molecules that inhibit intermixing between compartments. However, our present understanding of Hedgehog signalling from posterior to anterior cells raises some interesting alternative models based on a cell's response to signalling. We show here that anterior cells that lack smoothened, and thus the ability to receive the Hedgehog signal, no longer obey a lineage restriction in the normal position of the anterior-posterior boundary. Rather these clones extend into anatomically posterior territory, without any changes in engrailed/invected gene expression. We have also examined clones lacking both en and inv; these too show complex behaviors near the normal site of the compartment boundary, and do not always cross entirely into anatomically anterior territory. Our results suggest that compartmentalization is a complex process involving intercompartmental signalling; models based on changes in affinity or growth will be discussed.

Animals↗

PubMed2001

Ventilatory modes and mechanics of the hedgehog skate (Leucoraja erinacea): testing the continuous flow model.

The movement of water across the gills of non-ram-ventilating fishes involves the action of two pumps: a pressure pump that pushes water across the gills from the oropharyngeal to the parabranchial cavity, and a suction pump that draws water across the gills from the oropharyngeal into the parabranchial cavity. Together, the two are thought to keep water flowing continuously anteroposteriorly through the head of the respiring animal. However, there is evidence that the pressure and suction pumps do not always work in perfect phase in elasmobranch fishes, leading to periods of higher pressure in the parabranchial than in the oropharyngeal cavity. We investigated the existence and consequence of such pressure reversals in the hedgehog skate Leucoraja erinacea using pressure transducers, sonomicrometry and flow visualization including internal visualization using endoscopy. We noted four patterns of respiration in the experimental skates distinguished by the flow pattern at the three openings into the respiratory system: (1) in through the spiracle only, (2) in through the mouth + spiracle, (3) in through the mouth only, and (4) the mouth held open throughout the respiratory cycle. The first two were by far the dominant modes recorded from experimental animals. We determined that pressure reversals exist in the hedgehog skate, and that the gill bars adducted during such pressure reversals. Direct observation confirmed that these pressure reversals do correspond to pulsatile flow across the gills. During mouth+spiracle ventilation the flow completely reversed direction, flowing from the parabranchial chambers back across the gills and into the oropharyngeal cavity. Finally, we addressed the utility of sonomicrometry as a technique for determining kinematics in aquatic animals. Despite some problems involving errors inherent to the system design, we found the technique useful for complementing such techniques as pressure measurements and endoscopy.

Animals↗

PubMed1999

Sonic hedgehog promotes neuronal differentiation of murine spinal cord precursors and collaborates with neurotrophin 3 to induce Islet-1.

Sonic hedgehog (Shh) is strongly implicated in the development of ventral structures in the nervous system. Addition of Sonic hedgehog protein to chick spinal cord explants induces floor plate and motoneuron development. Whether Shh acts directly to induce these cell types or whether their induction is mediated by additional factors is unknown. To further investigate the role of Shh in spinal neuron development, we have used low-density cultures of murine spinal cord precursor cells. Shh stimulated neuronal differentiation; however, it did not increase the proportion of neurons expressing the first postmitotic motoneuron marker Islet-1. Moreover, Shh did induce Islet-1 expression in neural tube explants, suggesting that it acts in combination with neural tube factors to induce motoneurons. Another factor implicated in motoneuron development is neurotrophin 3 (NT3), and when assayed in isolated precursor cultures, it had no effect on Islet-1 expression. However, the combination of N-terminal Shh and NT3 induced Islet-1 expression in the majority of neurons in low-density cultures of caudal intermediate neural plate. Furthermore, in explant cultures, Shh-mediated Islet-1 expression was blocked by an anti-NT3 antibody. Previous studies have shown expression of NT3 in the region of motoneuron differentiation and that spinal fusimotor neurons are lost in NT3 knock-out animals. Taken together, these findings suggest that Shh can act directly on spinal cord precursors to promote neuronal differentiation, but induction of Islet-1 expression is regulated by factors additional to Shh, including NT3.

Animals↗

PubMed1996

[Effect of hedgehog hydnum on the delay of fatigue in mice].

Two groups of mice were fed with either hedgehog hydnum powder or extract for sixty days. For the assay of fatigue, the activity of serum lactate dehydrogenase, the serum urea nitrogen content, blood lactic acid, hepatic and muscular glycogen, and the physical stamina of the mice were determined. The activity of serum lactate dehydrogenase and the hepatic and muscular glycogen content in the experimental mice were evidently higher than that in the control mice (P < 0.05 or P < 0.01). After exercise, the increase in blood lactic acid and serum urea nitrogen in the experimental mice was significantly lower than that in the control mice (P < 0.05 or P < 0.01), but the rate of elimination of blood lactic acid in the experimental mice was significantly higher than that in the control mice (P < 0.05). In the physical stamina swimming, the experimental mice drowned after a longer period of time than the control mice (P < 0.05). In conclusion hedgehog hydnum had a significant effect on raising physical stamina and delaying fatigue in mice.

Animals↗

PubMed1996

Efferents from the lateral frontal cortex to spinomedullary target areas, trigeminal nuclei, and spinally projecting brainstem regions in the hedgehog tenrec.

This study was done in the Madagascan lesser hedgehog tenrec, an insectivore with a very poorly differentiated neocortex. The cortical region, known to give rise to spinal projections, was injected with tracer, and the cortical efferents to brainstem and spinal cord were analyzed. Bulbar reticular fields, in addition, were identified according to their cells of origin and the laterality of their spinal projections after injection of tracer. Only few cortical fibers could be traced from the bulbar pyramid into the ipsilateral spinal cord, particularly to the lateral funiculus. The projections to the dorsal column nuclei and the classical spinally projecting brainstem regions were also weak. Faint projections were demonstrated to the nucleus of the posterior commissure and the nucleus of Darkschewitsch. In comparison to other mammals, there was no evidence that the contralateral cortico-bulbo-spinal pathway was strengthened, substituting for the almost non-existent contralateral corticospinal projection. Unlike the sensorimotor apparatus controlling limb and body movements, the brainstem regions controlling the head and neck received prominent cortical projections. Direct corticotrigeminal projections and indirect pathways were well represented. The projections to the trigeminal nuclei and the lateral reticular fields were clearly bilateral; those to the superior colliculus were predominantly ipsilateral. The corticobulbar fibers left the pyramid along its entire extent; the principal trigeminal nucleus and the dorsolateral pontine tegmentum were supplied by additional fibers of the corticotegmental tract. The lateral frontal cortex also projected densely to the dorsolateral hypothalamus, the periaqueductal gray, and the adjacent mesencephalic tegmentum, components of the emotional motor system.

Animals↗

PubMed1998

Thalamic territories innervated by cerebellar nuclear afferents in the hedgehog tenrec, Echinops telfairi.

To gain more insight into the evolution and functional significance of cerebrocerebellar circuits, the cerebellothalamic projections were studied with anterograde tracer substances in the Madagascan lesser hedgehog, tenrec. This insectivore shows one of the lowest size indices among mammals for both the cerebellar nuclei and the neocortex. Almost all cerebellodiencephalic target areas found in the tenrec have been described in other mammals. The intensity and extent of particular projections, however, vary considerably in the tenrec compared with the other mammals investigated so far. The most remarkable finding may be the tenrec's cerebellar projection to the nucleus ventralis medialis. This projection is the most prominent cerebellothalamic projection and originates in predominantly the lateral portion of the cerebellar nuclear complex. The projection to the caudolateral portion of the ventralis anterior complex (VAC) is located immediately rostral to the area receiving ascending somatosensory afferents and appears to originate, in particular, from the intermediate cerebellar nuclear complex. Another cerebellothalamic focus of terminations lies in the paralamellar region of the VAC, whereas the proper intralaminar nuclei, at best, receive a sparse cerebellar input. A faint-to-moderate projection, on the other hand, has been traced consistently to the ventral portion of the lateralis posterior-pulvinar complex and the adjacent dorsal geniculate nucleus. In addition, there are prominent cerebellosubthalamic projections to the zona incerta and the ventral geniculate nucleus. The latter projection is confined mainly to the ventralmost subdivision, which has been shown previously to receive ascending somatosensory, but not retinal, afferents. With the exception of the nucleus ventralis medialis, the projections were essentially confined to the contralateral side.

Afferent Pathways↗

PubMed1999

Expression of sonic hedgehog, patched, and Gli1 in developing taste papillae of the mouse.

Lingual taste buds form within taste papillae, which are specialized structures that develop in a characteristic spatial and temporal pattern. To investigate the signaling events responsible for patterning and morphogenesis of taste papillae, the authors examined the time course and distribution of expression of several related developmental signaling genes as well as the time course of innervation of taste papillae in mouse embryos from embryonic day 12 (E12) to E18. Lingual expression of the signaling molecule Sonic hedgehog (Shh), its receptor Patched (Ptc), and the Shh-activated transcription factor Gli1 were assayed by using in situ hybridization. Shh is expressed broadly in the lingual epithelium at E12 but becomes progressively restricted to developing circumvallate and fungiform papillary epithelia. Shh is expressed specifically within the central cells of the papillary epithelium starting at E13.5 and persisting through E18. Ptc and Gli1 expression follow a pattern similar to that of Shh. Compared with Shh, Ptc is expressed in larger regions surrounding the central papillary cells and also in the mesenchyme underlying Shh-expressing epithelium. Innervation of taste papillae was examined by using the panneuronal antibody to ubiquitin carboxyl terminal hydrolase (protein gene product 9.5). Nerves reach the basal lamina of developing taste papillae at E14 to densely innervate the papillary epithelium by E16. Thus, the pattern of Shh expression within developing taste papillae is established prior to innervation, ruling out neuronal induction of papillae. The results suggest that the Shh signaling pathway may be involved in: 1) establishing papillary boundaries in taste papilla morphogenesis, 2) papillary epithelial-mesenchymal interactions, and/or 3) specifying the location or development of taste buds within taste papillae.

Animals↗

PubMed1999

Effects of prenatal cocaine exposure on embryonic expression of sonic hedgehog.

Cocaine use by pregnant women may adversely affect development and behavior in the exposed infants. Sonic hedgehog (shh) is a secreted protein that induces development of many structures in the embryo, including dopaminergic cells in the ventral midbrain, the limb buds, and eyes. Because prenatal cocaine exposure has been shown to adversely affect the morphogenesis of these and other systems, the present study was undertaken to test the hypothesis that maternal cocaine treatment would alter shh mRNA expression. Cocaine HCl (60 mg/kg i.p.) was administered to pregnant mice on gestational days 6-8, the time that immediately precedes the appearance of shh. Control dams received i.p. saline. Embryos from gestational days 9-11 were examined by in situ hybridization. The temporal and spatial patterns of shh expression were indistinguishable between embryos from cocaine- and saline-treated dams. Examination of forebrain, midbrain, and midbody spinal cord coronal sections failed to reveal any differences in the dorsoventral and mediolateral localization of shh. The distribution of mRNA for patched (ptc), the membrane receptor for shh, was also indistinguishable between both groups. Chick embryos were next used to examine the direct application of cocaine into the developing brain. Shh distribution was similarly unaffected in these chick embryos. These data show that maternal cocaine treatment during early neural tube development does not significantly alter the expression patterns of shh or ptc mRNA. Thus, congenital defects and behavioral abnormalities associated with maternal cocaine use do not appear to result from altered expression of the shh-ptc pathway.

Abnormalities, Drug-Induced↗

PubMed1996

Polarizing activity, Sonic hedgehog, and tooth development in embryonic and postnatal mouse.

Tooth development involves reciprocal epithelial-mesenchymal interactions, polarized growth, mesenchyme condensation, and complex morphogenetic events. Because these processes bear similarities to those occurring in the developing limb, we asked whether morphogenetic signals found in the limb also occur in the developing tooth. We grafted mouse embryo tooth germs to the anterior margin of host chick embryo wing buds and determined whether the dental tissues had polarizing activity. Indeed, the grafts induced supernumerary digits. Activity of both molar and incisor tooth germs increased from bud to cap stages and was maximal at late bell stage in newborn. With further development the polarizing activity began to decrease, became undetectable in adult molar mesenchyme but persisted in incisor mesenchyme, correlating with the fact that incisors grow throughout postnatal life while molars do not. When different portions of neonatal incisors were assayed, a clear proximo-distal gradient of activity was apparent, with maximal activity restricted to the most proximal portion where undifferentiated mesenchyme and enamel organ reside. In situ hybridizations demonstrated that prior to induction of supernumerary digits, the tooth germ grafts induced expression in host tissue of Hoxd-12 and Hoxd-13. In addition, whole-mount in situ hybridizations and immunohistochemistry showed that developing tooth germs express Sonic hedgehog (Shh). Shh expression was first detected in bud stage tooth germs; at later stages Shh transcripts were prominent in enamel knot and differentiating ameloblasts at the cuspal region. We concluded that tooth germs possess polarizing activity and produce polarizing factors such as Shh. As in the limb, these factor(s) and activity probably play key roles in establishing polarity and regulating morphogenesis during early tooth development. Given its subsequent association with differentiating ameloblasts, Shh probably participates also in cytogenetic events during odontogenesis.

Aging↗

PubMed1999

Msx1 is required for the induction of Patched by Sonic hedgehog in the mammalian tooth germ.

We have used the mouse developing tooth germ as a model system to explore the transmission of Sonic hedgehog (Shh) signal in the induction of Patched (Ptc). In the early developing molar tooth germ, Shh is expressed in the dental epithelium, and the transcripts of Shh downstream target genes Ptc and Gli1 are expressed in dental epithelium as well as adjacent mesenchymal tissue. The homeobox gene Msx1 is also expressed in the dental mesenchyme of the molar tooth germ at this time. We show here that the expression of Ptc, but not Gli1, was downregulated in the dental mesenchyme of Msx1 mutants. In wild-type E11.0 molar tooth mesenchyme SHH-soaked beads induced the expression of Ptc and Gli1. However, in Msx1 mutant dental mesenchyme SHH-soaked beads were able to induce Gli1 but failed to induce Ptc expression, indicating a requirement for Msx1 in the induction of Ptc by SHH. Moreover, we show that another signaling molecule, BMP4, was able to induce Ptc expression in wild-type dental mesenchyme, but induced a distinct expression pattern of Ptc in the Msx1 mutant molar mesenchyme. We conclude that in the context of the tooth germ Msx1 is a component of the Shh signaling pathway that leads to Ptc induction. Our results also suggest that the precise pattern of Ptc expression in the prospective tooth-forming region is controlled and coordinated by at least two inductive signaling pathways.

Animals↗

PubMed2000

hedgehog and wing development in Drosophila: a morphogen at work?

In Drosophila, Hedgehog (Hh) is a key regulator of limb development and activates decapentaplegic (dpp), a gene encoding a TGFbeta-related factor that controls growth and patterning of the limbs. During wing development, Hh also has morphogen-like Dpp-independent functions, controlling the morphogenesis of the central part of the wing through the activation of the evolutionarily conserved transcription factors encoded by the iroquois and collier genes. The ways in which Hh forms an activity gradient to lay the basis of patterning of the adult wing are described here. As the signal transduction pathway of Hh is strongly conserved during evolution and human Hh may be implicated in congenital diseases and cancers, these observations provide important advances which may help in understanding the function of Hh proteins in normal and pathological development and tumourigenesis in humans.

Animals↗