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Investigation of a modifier locus displaying a darker eye phenotype in white-apricot flies led to the isolation of the gene encoding UDP-glucose dehydrogenase (UDPGDH). The P-element insertion l(3)05007 occurs upstream of the transcription start site of the sugarless (sgl) gene and greatly reduces its transcription at various developmental stages. A single abundant sgl transcript shows a ubiquitous distribution and encodes a 53-kDa protein which is 64% identical in sequence to bovine UDP-glucose dehydrogenase. Overexpression of sgl in E. coli resulted in synthesis of a protein with high levels of UDPGDH activity. Expression of three genes that participate in pigment deposition, white, scarlet and brown, was significantly affected in populations segregating for sgl, suggesting that it is the decrease in UDPGDH level that produces the modifying effect observed. In addition, genetic effects on white-apricot were observed in sgl-wingless and sgl-hedgehog double mutants. Recent data have indicated an effect of UDPGDH on cell surface glycosaminoglycans (GAGs) which modulate the activity of growth factors, and in particular wingless signaling. Our results suggest that the levels of GAGs are rate limiting for cell-cell signaling pathways which mediate changes in gene expression.
Mol Gen Genet 1998 Nov
PMID:The sugarless mutation affects the expression of the white eye color gene in Drosophila melanogaster. 986 65

Sonic hedgehog (Shh) is a secreted glycoprotein expressed by the notochord and floor plate that is involved in the induction and specification of ventral phenotypes in the vertebrate neural tube. Recently, Shh has also been shown to promote the survival of cultured rat embryo ventral brain and spinal cord cells. We have examined whether Shh can promote the survival of chick embryo neurons in vivo or in vitro. In the chick, Shh is expressed in notochord, floor plate, and ventral neural tube/spinal cord at several stages at which programmed cell death (PCD) occurs. However, the administration of exogenous Shh to embryos in vivo or to motoneuron cultures at these stages failed to promote the survival of several different neuronal populations, including spinal motoneurons, spinal interneurons, sympathetic preganglionic neurons, sensory neurons, and neuronal precursor cells. Rather, at the earliest stage of PCD examined here (embryonic day 3) Shh selectively induced the death of ventral neuronal precursors and floor-plate cells, resulting in a net loss of cells in the neural tube. Altered concentrations of Shh induce aberrant phenotypes that are removed by PCD. Accordingly, normal PCD in the early neural tube may play a role in dorsal-ventral patterning.
Mol Cell Neurosci 1999 May
PMID:Modulation of early but not later stages of programmed cell death in embryonic avian spinal cord by sonic hedgehog. 1035 97

Holoprosencephaly (HPE), the most common developmental defect of the forebrain and the face, is genetically heterogeneous. One of the genes involved, Sonic hedgehog ( SHH ), on 7q36, has been identified as the first HPE-causing gene both in mouse and humans. In order to delineate the phenotype of specific SHH mutations, we described the expression of the SHH gene during early human embryogenesis and investigated the phenotype of novel SHH mutations. In situ hybridization studies were performed on paraffin-embedded human embryo sections at three different development stages. These studies show that SHH is expressed in the notochord, the floorplate, the brain, the zone of polarizing activity and the gut. We also report on the phenotype of four novel mutations identified in 40 HPE families (two in isolated HPE and two in familial HPE). Expressivity ranged from alobar HPE to microcephaly and hypoplasia of the pituitary gland in one family, and from HPE to an asymptomatic form in another family. No SHH mutation was found in six polymalformed cases combining HPE with other defects, such as skeletal, limb, cardiac, anal and/or renal anomalies. This study confirms the genetic heterogeneity of HPE, and further demonstrates that SHH mutations are associated with a broad spectrum of cerebral midline defects.
Hum Mol Genet 1999 Sep
PMID:Expression of the Sonic hedgehog (SHH ) gene during early human development and phenotypic expression of new mutations causing holoprosencephaly. 1044 31

The rab GDP-dissociation inhibitor (rab GDI) proteins are involved in the regulation of vesicle-mediated cellular transport. We isolated the amphioxus rab GDI gene, analyzed its expression during amphioxus development, and performed a phylogenetic analysis of the rab GDI family. In contrast to the two major rab GDI forms in mammals, the alpha and beta forms, there is only one rab GDI isoform in amphioxus. Our analysis indicates that the occurrence of the alpha and beta forms of rab GDI preceded the divergence of lineages leading to birds and mammals, and that the amphioxus rab GDI may have evolved directly from the common ancestor of both forms. While the mammalian rab GDI beta-genes are ubiquitously expressed, the rab GDI alpha genes are predominantly expressed in neural tissues. The expression analysis of the amphioxus rab GDI gene shows predominantly neural expression similar to that of the mammalian rab GDI alpha form, suggesting that the ancestral expression pattern of chordate rab GDI was neural. In addition, the chicken rab GDI beta-like gene also shows neural-specific expression, which indicates that the neural expression was retained in both early postduplication alpha and beta isoforms and that a novel function associated with ubiquitous expression may have evolved uniquely in mammals. These results reveal a likely scenario of functional divergence of the rab GDI genes after duplication of the ancestral gene. A similar pattern of evolution, in which one of the duplicated genes retained a role similar to that of the ancestral one while other genes were recruited into novel roles, was also observed in the analysis of chordate Otx and hedgehog genes. In the rab GDI, hedgehog, and Otx gene families, the gene retaining the ancestral role shows a lower rate of sequence evolution than its counterpart, which was recruited for a novel function.
Mol Biol Evol 1999 Sep
PMID:The amphioxus rab GDP-dissociation inhibitor (GDI) gene is neural-specific: implications for the evolution of chordate rab GDI genes. 1048 78

Numerous naturally-occurring and synthetic compounds that were discovered initially because of their toxic properties, were later shown to possess biological activities beneficial to humans that enabled them to serve as templates for the development of useful medicinal agents. A prominent example is thalidomide, a synthetic drug that gained notoriety originally due to its catastrophic teratogenicity in humans. The discovery of thalidomide's efficacy in treating several diseases has resulted in the recrudescence of the drug to society's usage. A current example of this phenomenon is the plant teratogen cyclopamine (11-deoxojervine), whose deleterious terata-inducing effects were restricted to grazing animals, but whose recently discovered inhibition of Sonic hedgehog signal transduction has provided both the potential to increase our understanding of organogenesis and to serve as a lead compound in drug development.
Cell Mol Biol (Noisy-le-grand) 1999 Jul
PMID:A looking glass perspective: thalidomide and cyclopamine. 1051 90

Holoprosencephaly (HPE) is the most common developmental defect of the forebrain in humans. Several distinct human genes for holoprosencephaly have now been identified. They include Sonic hedgehog (SHH), ZIC2, and SIX3. Many additional genes involved in forebrain development are rapidly being cloned and characterized in model vertebrate organisms. These include Patched (Ptc), Smoothened (Smo), cubitus interuptus (ci)/Gli, wingless (wg/Wnt, decapentaplegic (dpp)/BMP, Hedgehog interacting protein (Hip), nodal, Smads, One-eyed pinhead (Oep), and TG-Interacting Factor (TGIF). However, further analysis is needed before their roles in HPE can be established. Here we present an overview of the presently known genes causing human holoprosencephaly and describe candidate genes involved in forebrain development identified in other systems. A model is discussed for how these genes may interact within and between several different signaling pathways to direct the formation of the forebrain.
Mol Genet Metab 1999 Oct
PMID:Molecular mechanisms of holoprosencephaly. 1052 64

Hereditary multiple exostoses (HME) is an autosomal dominant condition in which bony outgrowths occur from the juxtaepiphyseal regions of the long bones. In a few percent of cases these exostoses undergo malignant transformation to chondrosarcomas. HME results from mutations in one of two homologous genes, EXT1 and EXT2. These are members of a new gene family that is conserved from Caenorhabditis elegans to higher vertebrates. In humans this family comprises five genes which are most conserved at their C-termini, but they do not contain any discernible functional motifs and their function(s) is unclear. Indirect evidence suggests that EXT proteins are involved in glycosaminoglycan synthesis, act as tumor suppressors and affect hedgehog signaling. One recent study has also reported that these proteins co-purify with glycosyltransferase (GlcA and GlcNAc transferase) activity and on that basis it has been postulated that they are themselves glycosyl-transferases. We performed two-hybrid screens with a fragment of EXT2 from the region that is most highly conserved in the gene family and identified two interacting proteins: the tumor necrosis factor type 1 associated protein and a novel UDP-GalNAc:poly-peptide N -acetylgalactosaminyltransferase. Significantly, both these interactions were abrogated by a disease-causing EXT mutation, indicating that they are important in the etiology of HME. The EXT2-GalNAc-T5 interaction provides the first direct physical link between EXT proteins and known components of glycosamino-glycan synthesis.
Hum Mol Genet 1999 Nov
PMID:A direct interaction between EXT proteins and glycosyltransferases is defective in hereditary multiple exostoses. 1054 94

The complete mitochondrial (mt) genome of the mole Talpa europaea was sequenced and included in phylogenetic analyses together with another lipotyphlan (insectivore) species, the hedgehog Erinaceus europaeus, and 22 other eutherian species plus three outgroup taxa (two marsupials and a monotreme). The phylogenetic analyses reconstructed a sister group relationship between the mole and fruit bat Artibeus jamaicensis (order Chiroptera). The Talpa/Artibeus clade constitutes a sister clade of the cetferungulates, a clade including Cetacea, Artiodactyla, Perissodactyla, and Carnivora. A monophyletic relationship between the hedgehog and the mole was significantly rejected by maximum parsimony and maximum likelihood. Consistent with current systematic schemes, analyses of complete cytochrome b genes including the shrew Sorex araneus (family Soricidae) revealed a close relationship between Talpidae and Soricidae. The analyses of complete mtDNAs, along with the findings of other insectivore studies, challenge the maintenance of the order Lipotyphla as a taxonomic unit and support the elevation of the Soricomorpha (with the families Talpidae and Soricidae and possibly also the Solenodontidae and Tenrecidae) to the level of an order, as previously proposed in some morphological studies.
Mol Biol Evol 2000 Jan
PMID:The phylogenetic position of the Talpidae within eutheria based on analysis of complete mitochondrial sequences. 1066 6

CREB-binding protein (CBP) serves as a transcriptional coactivator in multiple signal transduction pathways. The Drosophila homologue of CBP, dCBP, interacts with the transcription factors Cubitus interruptus (CI), MAD, and Dorsal (DL) and functions as a coactivator in several signaling pathways during Drosophila development, including the hedgehog (hh), decapentaplegic (dpp), and Toll pathways. Although dCBP is required for the expression of the hh target genes, wingless (wg) and patched (ptc) in vivo, and potentiates ci-mediated transcriptional activation in vitro, it is not known that ci absolutely requires dCBP for its activity. We used a yeast genetic screen to identify several ci point mutations that disrupt CI-dCBP interactions. These mutant proteins are unable to transactivate a reporter gene regulated by ci binding sites and have a lower dCBP-stimulated activity than wild-type CI. When expressed exogenously in embryos, the CI point mutants cannot activate endogenous wg expression. Furthermore, a CI mutant protein that lacks the entire dCBP interaction domain functions as a negative competitor for wild-type CI activity, and the expression of dCBP antisense RNAs can suppress CI transactivation in Kc cells. Taken together, our data suggest that dCBP function is necessary for ci-mediated transactivation of wg during Drosophila embryogenesis.
Mol Cell Biol 2000 Mar
PMID:Cubitus interruptus requires Drosophila CREB-binding protein to activate wingless expression in the Drosophila embryo. 1066 39

Phylogenetic analysis of protease domains of the vertebrate plasminogen-prothrombin family revealed two major subfamilies: (1) a subfamily containing macrophage-stimulating protein (MSP), hepatocyte growth factor (HGF), plasminogen, and apolipoprotein(a) (APOA); and (2) a subfamily containing prothrombin, HGF activator, and plasminogen activators. There was evidence that these two subfamilies diverged prior to the divergence of amphibians and amniotes. The phylogeny indicated a close relationship of APOA from the European hedgehog, rhesus monkey, and human with plasminogen. Phylogenetic analysis of repeated kringle domains supported the hypothesis that APOA evolved independently in hedgehog and primates through numerous duplications of different kringle domains of the ancestral plasminogen. Phylogenies of kringle domains revealed two modes of evolution: (1) a conservative mode, whereby duplication of kringle domains occurred prior to cladogenesis and the same kringle structure has been maintained in different lineages (exemplified by plasminogen and prothrombin); and (2) a concerted mode, whereby kringle domains have duplicated since cladogenesis and thus orthologous relationships do not exist between kringles of different lineages (exemplified by APOA).
Mol Phylogenet Evol 2000 Mar
PMID:Modes of evolution in the protease and kringle domains of the plasminogen-prothrombin family. 1071 51


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