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PubMed2003

Defective sonic hedgehog signaling in esophageal atresia with tracheoesophageal fistula.

BACKGROUND: The pathogenesis of esophageal atresia and tracheoesophageal fistula (EA/TEF) remains unknown. We have found previously that an initial esophageal atresia, followed by an abnormal (absent) branching pattern of the middle branch of a trifurcation of the lung/tracheal bud, leads to the neonatal finding of TEF. Mice null mutant for hedgehog signaling can experience the development of EA/TEF, but the mechanism for this development is also unknown. Given that EA/TEF in humans appears not to be due to genetic defects, a hedgehog mutation cause seems very unlikely. However, defective hedgehog signaling that is caused by environmental effects in the human embryo likely could be implicated. We studied a teratogen-induced model of EA/TEF to determine the mechanism by which defective hedgehog signaling may lead to EA/TEF. METHODS: We injected Adriamycin into pregnant rats to induce EA/TEF in rat embryos. We first quantified sonic hedgehog (Shh) signaling pathway molecule expression using real-time, semiquantitative reverse-transcriptase polymerase chain reaction for Shh, Shh receptors (patched and smoothened), and downstream intracellular targets of those receptors (Gli family members). On the basis of these findings, we then developed an in vitro culture system for the day-12 embryonic TEF and manipulated Shh signaling using either exogenous Shh or Shh inhibitors. RESULTS: By reverse transcriptase-polymerase chain reaction, a unique difference between the fistula tract and control tissues was that Gli-2 (downstream signaling molecule of Shh) messenger RNA levels were much lower in the fistula tract than in the adjacent esophagus (P =.002). Surprisingly, in the culture experiments, the fistula tract was induced to branch by exogenous Shh. Such branching of the fistula was unexpected and further supports the presumed respiratory origin of the fistula tract because the normal lung, but not normal esophagus, branched in response to Shh. The Shh inhibitor had no effect, which indicated that defective signaling, rather than hyperfunctioning Shh, is critical to the nonbranching phenotype of the fistula tract in TEF. CONCLUSIONS: The recapitulation of respiratory developmental morphogenesis by the fistula tract of TEF in the presence of exogenous Shh, together with the quantitative reduction in normal, endogenous levels of Gli-2, strongly suggests that 1 mechanism for the formation of the fistula tract is the lack of proper Shh signaling because of Gli-2 deficiency, with subsequent straight, nonbranching caudal growth of the fistula tract. This deficiency can be rescued by excess exogenous Shh, thus reestablishing respiratory morphogenesis.

Animals↗
PubMed2003

Identification of a novel apolipoprotein(a)-related protein from the European hedgehog (Erinaceus europaeus).

We have isolated a cDNA encoding an apo(a)-related protein designated HaRP-1 (Hedgehog apo(a) related protein-1). The HaRP-1 cDNA (2114 bp; corresponding to a 2.6 kb transcript) was isolated from a hedgehog liver cDNA library. The HaRP-1 clone corresponded to an open reading frame of 676 amino acids and contains a signal sequence followed by a preactivation domain and 7 kringle domains which exhibit an average of 57% amino acid identity with hedgehog plasminogen kringle III. We expressed HaRP-1 in human embryonic kidney cells; immunoprecipitation of metabolically-labeled conditioned medium from transfected cells showed the presence of a 74 kDa band corresponding to HaRP-1. Of note, we also observed an approximately 72 kDa species present in hedgehog plasma by western blotting using a human anti-apo(a) monoclonal antibody; we speculate that the 72 kDa plasma species corresponds to HaRP-1. Interestingly, although none of the 7 kringle domains contained a canonical lysine-binding site, we found that recombinant HaRP-1 bound specifically to lysine-Sepharose. It is likely that the evolution of the HaRP-1 gene is coincident with the evolution of hedgehog apo(a), both of which occurred by duplication of the plasminogen kringle III motif. The function of HaRP-1 remains unclear at present, but may constititute a member of the family of apo(a) proteins that functions in the regulation of lysine-dependent proteolysis.

Amino Acid Sequence↗
PubMed1997

Positive and negative regulation of muscle cell identity by members of the hedgehog and TGF-beta gene families.

We have examined whether the development of embryonic muscle fiber type is regulated by competing influences between Hedgehog and TGF-beta signals, as previously shown for development of neuronal cell identity in the neural tube. We found that ectopic expression of Hedgehogs or inhibition of protein kinase A in zebrafish embryos induces slow muscle precursors throughout the somite but muscle pioneer cells only in the middle of the somite. Ectopic expression in the notochord of Dorsalin-1, a member of the TGF-beta superfamily, inhibits the formation of muscle pioneer cells, demonstrating that TGF-beta signals can antagonize the induction of muscle pioneer cells by Hedgehog. We propose that a Hedgehog signal first induces the formation of slow muscle precursor cells, and subsequent Hedgehog and TGF-beta signals exert competing positive and negative influences on the development of muscle pioneer cells.

Animals↗
PubMed2006

Analysis of Nsdhl-deficient embryos reveals a role for Hedgehog signaling in early placental development.

The X-linked Nsdhl gene encodes a sterol dehydrogenase involved in cholesterol biosynthesis. Mutations in this gene cause the male lethal phenotypes in human CHILD syndrome and bare patches (Bpa) mice. Affected male embryos for several mutant Nsdhl alleles die in mid-gestation with a thin and poorly vascularized placental labyrinth. The timing and specific abnormalities noted suggest a defect in one or more developmental signaling pathways as a possible mechanism. Here, we examined the possible involvement of the hedgehog signaling pathway in the placental pathology of Nsdhl mutants using a transgenic mouse line (Ptch1(tm1Mps)) that contains a lacZ reporter under the control of the promoter for Ptch1, the gene that encodes the major hedgehog receptor. We demonstrate expression of Ptch1 in allantoic mesoderm of the placenta from wild-type mid-gestation embryos. The evidence suggests that the signaling is induced by Indian hedgehog that is produced by distal (ectoplacental) visceral endoderm cells that migrate into the allantoic mesoderm before embryonic day 10.0. Using a ubiquitously expressed, X-linked lacZ transgene that undergoes normal X-inactivation, we demonstrate that the placental defects in Nsdhl/+ female embryos are non-cell autonomous. Further, affected placentas from mutant Nsdhl(Bpa-8H) male embryos demonstrate markedly decreased or no Ptch1-lacZ staining and no migration of Ihh expressing cells into the developing placenta. These data strongly implicate the hedgehog signaling pathway in the pathogenesis of the placental defects in NSDHL deficiency and provide evidence for a role for the hedgehog pathway in the development of a functional mammalian placenta.

3-Hydroxysteroid Dehydrogenases↗
PubMed1995

Xenopus sonic hedgehog as a potential morphogen during embryogenesis and thyroid hormone-dependent metamorphosis.

The hedgehog family of proteins have been implicated as important signaling molecules in establishing cell positional information and tissue patterning. Here we present the cloning and characterization of a hedgehog homologue from Xenopus laevis similar to the sonic class of vertebrate hedgehog genes. We isolated Xenopus hedgehog (Xhh) from a subtractive hybridization screen designed to identify genes induced by thyroid hormone during metamorphosis of the X.laevis gastrointestinal tract. In the intestine, Xhh mRNA expression was up-regulated at the climax of metamorphosis (stage 62) when intestinal epithelium underwent morphogenesis. Treatment of pre-metamorphic tadpoles with exogenous thyroid hormone (TH) resulted in a similar pattern of Xhh induction. Furthermore, TH induction was resistant to inhibitors of protein synthesis suggesting that Xhh is a direct thyroid hormone response gene. The expression and TH regulation of Xhh was not limited to the intestine, but was also observed in the limb and a mixture of pancreas and stomach. Throughout development, Xhh mRNA was present at varying levels with the earliest expression being detected at neurula stage. The highest levels of Xhh were observed between stages 33 and 40 shortly before tadpole feeding begins. Whole mount in situ hybridization analysis of Xhh expression in pre-hatching, stage 32 tadpoles demonstrated staining in the notochord and floor plate similar to that observed for other vertebrate hedgehog genes. Together, these data suggest a putative role for Xhh in organ development during both amphibian embryogenesis and metamorphosis.

Aging↗
PubMed2003

Sonic hedgehog is a neuromodulator in the adult subthalamic nucleus.

It is well established that members of the hedgehog family are involved in tissue patterning during development. We herein show that sonic hedgehog signaling molecules are differentially regulated by dopamine depletion in the basal ganglia of adult animals and specifically that sonic hedgehog levels are reduced in an animal model of Parkinson's disease. In addition, we show that sonic hedgehog protein inhibits electrical activity in the subthalamic nucleus, a key element of basal ganglia, within minutes of application. As the subthalamic nucleus is overactive in parkinsonism, we suggest that enhancement of sonic hedgehog signaling in the subthalamic nucleus may be of therapeutic value in Parkinson's disease.

Animals↗
PubMed2006

Differential regulation of tyrosine hydroxylase expression by sonic hedgehog.

Sonic hedgehog functions to induce floor plate in early stages, and spinal motor neurons and midbrain dopaminergic neurons in later stages of development. Here, we investigated the effects of sonic hedgehog on tyrosine hydroxylase expression in three cell lines that correspond to different stages of neural development. Sonic hedgehog increased the tyrosine hydroxylase gene expression in pluripotent P19 cells but repressed it in tyrosine hydroxylase-producing PC12 cells. Promoter analysis in mouse neural stem cells indicated that the N-terminal of sonic hedgehog repressed both the basal and cAMP-dependent protein kinase A-mediated tyrosine hydroxylase activity. These results suggest that the N-terminal of sonic hedgehog increases tyrosine hydroxylase gene expression in cells to acquire dopaminergic phenotypes, but decreases expression in late born neurons by antagonizing the protein kinase A cAMP-responsive element binding protein pathway.

Animals↗
PubMed2006

Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells.

The epithelial components of the mammary gland are thought to arise from stem cells with a capacity for self-renewal and multilineage differentiation. Furthermore, these cells and/or their immediate progeny may be targets for transformation. We have used both in vitro cultivation and a xenograft mouse model to examine the role of hedgehog signaling and Bmi-1 in regulating self-renewal of normal and malignant human mammary stem cells. We show that hedgehog signaling components PTCH1, Gli1, and Gli2 are highly expressed in normal human mammary stem/progenitor cells cultured as mammospheres and that these genes are down-regulated when cells are induced to differentiate. Activation of hedgehog signaling increases mammosphere-initiating cell number and mammosphere size, whereas inhibition of the pathway results in a reduction of these effects. These effects are mediated by the polycomb gene Bmi-1. Overexpression of Gli2 in mammosphere-initiating cells results in the production of ductal hyperplasia, and modulation of Bmi-1 expression in mammosphere-initiating cells alters mammary development in a humanized nonobese diabetic-severe combined immunodeficient mouse model. Furthermore, we show that the hedgehog signaling pathway is activated in human breast "cancer stem cells" characterized as CD44+CD24-/lowLin-. These studies support a cancer stem cell model in which the hedgehog pathway and Bmi-1 play important roles in regulating self-renewal of normal and tumorigenic human mammary stem cells.

Animals↗
PubMed1992

Bilateral thalamocortical projection in hedgehogs: evolutionary implications.

In adult hedgehogs with large unilateral cortical deposits of fluorescent somatopetal tracers, labelled perikarya were found not only in the ipsilateral but also contralateral thalamus. An exceptionally large number of contralaterally labelled neurons was seen in the ventrolateral nucleus, also at a considerable distance from the midline. Deposits of one of two different tracers in the frontoparietal cortex of each hemisphere appear to label different perikarya in each ventrolateral nucleus. This projection to the contralateral cortex in hedgehogs does not resemble thalamo-cortical connections in either adult or developing brains of other mammalian species. Among amniotes, only in pigeons have contralateral projections from the thalamus to the telencephalon been described. The somatosensorimotor system of hedgehogs may be the only known mammalian remnant of primitive vertebrate thalamocortical organization. Whether primitive or derived, the bilateral thalamocortical projection in hedgehogs shows that hedgehog brains cannot be uncritically taken to represent brains of primate ancestors.

Animals↗
PubMed2002

Hedgehog signal transduction proteins: contacts of the Fused kinase and Ci transcription factor with the kinesin-related protein Costal2.

BACKGROUND: Hedgehog signaling proteins play important roles in development by controlling growth and patterning in various animals including Drosophila and mammals. Hedgehog signaling triggers changes in responsive cells through a novel transduction mechanism that ultimately controls the transcription of specific target genes via the activity of zinc finger transcription factors of the Cubitus interruptus/GLI family. In flies, key Hedgehog signal transduction components have been identified including the kinesin-related protein Costal2, the serinethreonine kinase Fused, and the PEST-containing protein Suppressor of Fused. These proteins control Cubitus interruptus cleavage, nucleo-cytoplasmic localization and activation. In fly embryos, Costal2, Fused, Suppressor of Fused and Cubitus interruptus are associated in at least one cytoplasmic complex, which interacts with the microtubules in a Hedgehog-dependent manner. RESULTS: Here we identified and mapped direct interactions between Cos2, Fu, and Ci using an in vitro affinity assay and the yeast two-hybrid system. CONCLUSIONS: Our results provide new insights into the possible mechanism of the cytosolic steps of Hedgehog transduction.

Animals↗
PubMed1995

groucho and hedgehog regulate engrailed expression in the anterior compartment of the Drosophila wing.

Drosophila imaginal discs are divided into units called compartments. Cells belonging to the same compartment are related by lineage and express a characteristic set of 'selector genes'. The borders between compartments act as organizing centres that influence cell growth within compartments. Thus, in the cells immediately anterior to the anterior-posterior compartment boundary the presence of the hedgehog product causes expression of decapentaplegic, which, in turn, influences the growth and patterning of the wing disc. The normal growth of the disc requires that posterior-specific genes, such as hedgehog and engrailed are not expressed in cells of the anterior compartment. Here we show that hedgehog can activate engrailed in the anterior compartment and that both hedgehog and engrailed are specifically repressed in anterior cells by the activity of the neurogenic gene groucho. In groucho mutant discs, hedgehog and engrailed are expressed at the dorsoventral boundary of the anterior compartment, leading to the ectopic activation of decapentaplegic and patched and to a localised increase in cell growth associated with pattern duplications. The presence of engrailed in the anterior compartment causes the transformation of anterior into posterior structures.

Animals↗
PubMed1995

patched overexpression alters wing disc size and pattern: transcriptional and post-transcriptional effects on hedgehog targets.

The membrane protein, Patched, plays a critical role in patterning embryonic and imaginal tissues in Drosophila. patched constitutively inactivates the transcription of target genes such as wingless, decapentaplegic, and patched itself. The secreted protein, Hedgehog, induces transcription of target genes by opposing the Patched signaling pathway. Using the Gal4 UAS system we have overexpressed patched in wing imaginal discs and found that high Patched levels, expressed in either normal or ectopic patterns, result in loss of wing vein patterning in both compartments centering at the anterior/posterior border. In addition, patched inhibits the formation of the mechanosensory neurons, the campaniform sensilla, in the wing blade. The patched wing vein phenotype is modulated by mutations in hedgehog and cubitus interruptus (ci). Patched overexpression inhibits transcription of patched and decapentaplegic and post-transcriptionally decreases the amount of Ci protein at the anterior/posterior boundary. In hedgehogMrt wing discs, which express ectopic hedgehog, Ci levels are correspondingly elevated, suggesting that hedgehog relieves patched repression of Ci accumulation. Protein kinase A also regulates Ci; protein kinase A mutant clones in the anterior compartment have increased levels of Ci protein. Thus patched influences wing disc patterning by decreasing Ci protein levels and inactivating hedgehog target genes in the anterior compartment.

Animals↗
PubMed1995

Patterning of the neural ectoderm of Xenopus laevis by the amino-terminal product of hedgehog autoproteolytic cleavage.

The patterns of embryonic expression and the activities of Xenopus members of the hedgehog gene family are suggestive of role in neural induction and patterning. We report that these hedgehog polypeptides undergo autoproteolytic cleavage. Injection into embryos of mRNAs encoding Xenopus banded-hedgehog (X-bhh) or the amino-terminal domain (N) demonstrates that the direct inductive activities of X-bhh are encoded by N. In addition, both N and X-bhh pattern neural tissue by elevating expression of anterior neural genes. Unexpectedly, an internal deletion of X-bhh (delta N-C) was found to block the activity of X-bhh and N in explants and to reduce dorsoanterior structures in embryos. As elevated hedgehog activity increases the expression of anterior neural genes, and as delta N-C reduces dorsoanterior structures, these complementary data support a role for hedgehog in neural induction and anteroposterior patterning.

Animals↗
PubMed1999

hedgehog and engrailed: pattern formation and polarity in the Drosophila abdomen.

Like the Drosophila embryo, the abdomen of the adult consists of alternating anterior (A) and posterior (P) compartments. However the wing is made by only part of one A and part of one P compartment. The abdomen therefore offers an opportunity to compare two compartment borders (A/P is within the segment and P/A intervenes between two segments), and ask if they act differently in pattern formation. In the embryo, abdomen and wing P compartment cells express the selector gene engrailed and secrete Hedgehog protein whilst A compartment cells need the patched and smoothened genes in order to respond to Hedgehog. We made clones of cells with altered activities of the engrailed, patched and smoothened genes. Our results confirm (1) that the state of engrailed, whether 'off' or 'on', determines whether a cell is of A or P type and (2) that Hedgehog signalling, coming from the adjacent P compartments across both A/P and P/A boundaries, organises the pattern of all the A cells. We have uncovered four new aspects of compartments and engrailed in the abdomen. First, we show that engrailed acts in the A compartment: Hedgehog leaves the P cells and crosses the A/P boundary where it induces engrailed in a narrow band of A cells. engrailed causes these cells to form a special type of cuticle. No similar effect occurs when Hedgehog crosses the P/A border. Second, we look at the polarity changes induced by the clones, and build a working hypothesis that polarity is organised, in both compartments, by molecule(s) emanating from the A/P but not the P/A boundaries. Third, we show that both the A and P compartments are each divided into anterior and posterior subdomains. This additional stratification makes the A/P and the P/A boundaries fundamentally distinct from each other. Finally, we find that when engrailed is removed from P cells (of, say, segment A5) they transform not into A cells of the same segment, but into A cells of the same parasegment (segment A6).

Abdomen↗
PubMed2000

Transcriptional regulation of atonal required for Drosophila larval eye development by concerted action of eyes absent, sine oculis and hedgehog signaling independent of fused kinase and cubitus interruptus.

Bolwig's organ is the larval light-sensing system consisting of 12 photoreceptors and its development requires atonal activity. Here, we showed that Bolwig's organ formation and atonal expression are controlled by the concerted function of hedgehog, eyes absent and sine oculis. Bolwig's organ primordium was first detected as a cluster of about 14 Atonal-positive cells at the posterior edge of the ocular segment in embryos and hence, atonal expression may define the region from which a few Atonal-positive founder cells (future primary photoreceptor cells) are generated by lateral specification. In Bolwig's organ development, neural differentiation precedes photoreceptor specification, since Elav, a neuron-specific antigen, whose expression is under the control of atonal, is expressed in virtually all early-Atonal-positive cells prior to the establishment of founder cells. Neither Atonal expression nor Bolwig's organ formation occurred in the absence of hedgehog, eyes absent or sine oculis activity. Genetic and histochemical analyses indicated that (1) responsible Hedgehog signals derive from the ocular segment, (2) Eyes absent and Sine oculis act downstream of or in parallel with Hedgehog signaling and (3) the Hedgehog signaling pathway required for Bolwig's organ development is a new type and lacks Fused kinase and Cubitus interruptus as downstream components.

Animals↗
PubMed2001

The sex determination master switch, Sex-lethal, responds to Hedgehog signaling in the Drosophila germline.

Sex-lethal is the Drosophila melanogaster sex determination master switch. It is also required in female germ cells to control mitosis and meiotic recombination. As early germ cells mature, distinct changes in both Sex-lethal protein levels and localization occur. By manipulating the levels of Hedgehog and making germline clones of components in the hedgehog signaling pathway, we demonstrate that Hedgehog affects the nuclear translocation of Sex-lethal and the levels of the protein in early germ cells. This effect is mediated primarily through degradation. Consistent with the Hedgehog pathway regulating Sex-lethal, we find Sex-lethal in a complex with Fused and Costal-2, both downstream components of the pathway. This is the first demonstration that downstream components of the Hedgehog signaling pathway regulate a target other than Cubitus interruptus.

Animals↗
PubMed2001

Hedgehog signaling is required for pituitary gland development.

Pituitary gland development serves as an excellent model system in which to study the emergence of distinct cell types from a common primordium in mammalian organogenesis. We have investigated the role of the morphogen Sonic hedgehog (SHH) in outgrowth and differentiation of the pituitary gland using loss- and gain-of-function studies in transgenic mice. Shh is expressed throughout the ventral diencephalon and the oral ectoderm, but its expression is subsequently absent from the nascent Rathke's pouch as soon as it becomes morphologically visible, creating a Shh boundary within the oral epithelium. We used oral ectoderm/Rathke's pouch-specific 5' regulatory sequences (Pitx1(HS)) from the bicoid related pituitary homeobox gene (Pitx1) to target overexpression of the Hedgehog inhibitor Hip (Huntingtin interacting protein) to block Hedgehog signaling, finding that SHH is required for proliferation of the pituitary gland. In addition, we provide evidence that Hedgehog signaling, acting at the Shh boundary within the oral ectoderm, may exert a role in differentiation of ventral cell types (gonadotropes and thyrotropes) by inducing Bmp2 expression in Rathke's pouch, which subsequently regulates expression of ventral transcription factors, particularly Gata2. Furthermore, our data suggest that Hedgehog signaling, together with FGF8/10 signaling, synergizes to regulate expression of the LIM homeobox gene Lhx3, which has been proved to be essential for initial pituitary gland formation. Thus, SHH appears to exert effects on both proliferation and cell-type determination in pituitary gland development.

Animals↗
PubMed2000

Slow muscle induction by Hedgehog signalling in vitro.

Muscles are composed of several fibre types, the precise combination of which determines muscle function. Whereas neonatal and adult fibre type is influenced by a number of extrinsic factors, such as neural input and muscle load, there is little knowledge of how muscle cells are initially determined in the early embryo. In the zebrafish, fibres of the slow twitch class arise from precociously specified myoblasts that lie close to the midline whereas the remainder of the myotome differentiates as fast myosin expressing muscle. In vivo evidence has suggested the Sonic Hedgehog glycoprotein, secreted from the notochord, controls the formation of slow twitch and fast twitch muscle fates. Here we describe an in vitro culture system that we have developed to test directly the ability of zebrafish myoblasts to respond to exogenous Sonic Hedgehog peptide. We find that Sonic Hedgehog peptide can control the binary cell fate choice of embryonic zebrafish myoblasts in vitro. We have also used this culture system to assay the relative activities of different Hedgehog-family proteins and to investigate the possible involvement of heterotrimeric G-proteins in Hedgehog signal transduction.

Animals↗