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Hereditary osteochondromas are often caused by mutation in the EXT1 gene. The lesions are typified by formation of a "pseudo" growth plate like lesion growing at 60 degrees to the normal growth direction of the bone. Such lesions can be mimicked surgically by reverting the position--the polarity of the zone of LaCroix. The current study attempts to compare the pathology between EXT1 gene expression in humans and surgically created osteochondroma pathology in a rat model. Tissues of human bunion, human embryonal tissue, and human adult cartilage as well as normal rat epiphyses served as controls. Rats were operated on and a 60 degree span of the ring of LaCroix was inverted as described by Delgado (Delgado, E., Rodriguez, J. I., Serada, A., Tellez, M., and Pariagoa, R.. Clin. Orthop. 201, 251-258 (1985)). The surgically created osteochondromas were assessed by histology, histochemistry, and immunohistochemistry. The findings show that the surgically created lesions contain only a small amount of FGF receptor 3 (FGFR3) expressed on mesenchymal stem cells located in the perichondrium, as compared to the cell population carrying FGFR3 in the contralateral limb. Indian hedgehog and Bcl2 are downregulated, while BMP-2 is overexpressed in the operated limb, compared to the LaCroix ring of the contralaetral limb. The shortage, as well as the disturbed migration routes of the residual mesenchymal stem cells in surgically created osteochondromas leads eventually to resorption of the pathological elements. In search of additional markers characterizing such pathological structures composed of mesenchymal stem cells and cartilaginous and bony cells, EXT1 gene was found to be expressed in the surgically created osteochondromas, like in normal growth plates. Nitric oxide synthase was also expressed like in adult cartilage, though tumor necrosis factor alpha typifying Bunion formation was absent. In summary, surgically created osteochondromas lack the massive and continuous population of mesenchymal stem cells with Bcl2 expression. However, the small residual mesenchymal cell population gives rise to short-lived EXT1-expressing cells that disappear eventually due to spontaneous resorption.
Exp Mol Pathol 2003 Feb
PMID:The short-lived exostosis induced surgically versus the lasting genetic hereditary multiple exostoses. 1264 31

Lathosterol 5-desaturase catalyzes the conversion of lathosterol to 7-dehydrocholesterol in the next to last step of cholesterol synthesis. Inborn errors of cholesterol synthesis underlie a group of human malformation syndromes including Smith-Lemli-Opitz syndrome, desmosterolosis, CHILD syndrome, CDPX2 and lathosterolosis. We disrupted the lathosterol 5-desaturase gene (Sc5d ) in order to further our understanding of the pathophysiological processes underlying these disorders and to gain insight into the corresponding human disorder. Sc5d (-/-) pups were stillborn, had elevated lathosterol and decreased cholesterol levels, had craniofacial defects including cleft palate and micrognathia, and limb patterning defects. Many of the malformations found in Sc5d (-/-) mice are consistent with impaired hedgehog signaling, and appear to be a result of decreased cholesterol rather than increased lathosterol. A patient initially described as atypical SLOS with mucolipidosis was shown to have lathosterolosis by biochemical and molecular analysis. We identified a homozygous mutation of SC5D (137A>C, Y46S) in this patient. An unique aspect of the lathosterolosis phenotype is the combination of a malformation syndrome with an intracellular storage defect.
Hum Mol Genet 2003 Jul 01
PMID:Lathosterolosis: an inborn error of human and murine cholesterol synthesis due to lathosterol 5-desaturase deficiency. 1281 89

Cholesterol biosynthesis has been assumed to be an ubiquitous process in vertebrate organisms. Here we present data demonstrating that expression of key enzymes of cholesterol biosynthesis is restricted to specific tissues during embryonic development. Distinct expression starts in the dorsal neural tube at embryonic day 8 and is later detected in dorsal root and cephalic ganglia, in the pharyngeal pouches and limb buds. In the limb, expression becomes progressively restricted to interdigital regions during differentiation. Caspase3 whole mount immunostaining revealed that cholesterol biosynthesis colocalizes with apoptotic regions that are targets of the morphogenic signal Sonic hedgehog. This expression pattern correlates closely with the shared phenotypic features of cholesterol biosynthesis and hedgehog mutants.
Brain Res Mol Brain Res 2003 Jul 04
PMID:Embryonic expression of cholesterogenic genes is restricted to distinct domains and colocalizes with apoptotic regions in mice. 1282 59

Recent studies have demonstrated that oligodendrocyte progenitor (OLP) cells are induced from the ventral neural tube by the ventral midline signal, Sonic hedgehog (Shh). In this study, we investigated the role of Gli2 signal transducer in Shh induction of oligodendrocytes by studying oligodendrocyte development in Gli2-null mutants. In the absence of Gli2, the Olig1/2+ oligodendrogenic domain in the ventral spinal neuroepithelium is markedly reduced, and the initial production of OLP cells from the ventral neuroepithelium is much decreased and delayed. However, at late gestation stages, there is no discernible difference in the steady-state number of OLPs between the wild type and mutants. Interestingly, the initial delay and reduction of OLP production in the mutants is associated with a delayed expression of myelin-specific genes and oligodendrocyte differentiation. In contrast to oligodendrogenesis in the spinal cord, oligodendrocyte development in the forebrain is unaffected by Gli2 mutation. Together, our studies have suggested that Gli2 plays an important role in regulating oligodendrocyte specification and differentiation in the caudal neural tube.
Mol Cell Neurosci 2003 Jul
PMID:Gli2 is required for normal Shh signaling and oligodendrocyte development in the spinal cord. 1283 27

Higher-level relationships within, and the root of Placentalia, remain contentious issues. Resolution of the placental tree is important to the choice of mammalian genome projects and model organisms, as well as for understanding the biogeography of the eutherian radiation. We present phylogenetic analyses of 63 species representing all extant eutherian mammal orders for a new molecular phylogenetic marker, a 1.3kb portion of exon 26 of the apolipoprotein B (APOB) gene. In addition, we analyzed a multigene concatenation that included APOB sequences and a previously published data set (Murphy et al., 2001b) of three mitochondrial and 19 nuclear genes, resulting in an alignment of over 17kb for 42 placentals and two marsupials. Due to computational difficulties, previous maximum likelihood analyses of large, multigene concatenations for placental mammals have used quartet puzzling, less complex models of sequence evolution, or phylogenetic constraints to approximate a full maximum likelihood bootstrap. Here, we utilize a Unix load sharing facility to perform maximum likelihood bootstrap analyses for both the APOB and concatenated data sets with a GTR+Gamma+I model of sequence evolution, tree-bisection and reconnection branch-swapping, and no phylogenetic constraints. Maximum likelihood and Bayesian analyses of both data sets provide support for the superordinal clades Boreoeutheria, Euarchontoglires, Laurasiatheria, Xenarthra, Afrotheria, and Ostentoria (pangolins+carnivores), as well as for the monophyly of the orders Eulipotyphla, Primates, and Rodentia, all of which have recently been questioned. Both data sets recovered an association of Hippopotamidae and Cetacea within Cetartiodactyla, as well as hedgehog and shrew within Eulipotyphla. APOB showed strong support for an association of tarsier and Anthropoidea within Primates. Parsimony, maximum likelihood and Bayesian analyses with both data sets placed Afrotheria at the base of the placental radiation. Statistical tests that employed APOB to examine a priori hypotheses for the root of the placental tree rejected rooting on myomorphs and hedgehog, but did not discriminate between rooting at the base of Afrotheria, at the base of Xenarthra, or between Atlantogenata (Xenarthra+Afrotheria) and Boreoeutheria. An orthologous deletion of 363bp in the aligned APOB sequences proved phylogenetically informative for the grouping of the order Carnivora with the order Pholidota into the superordinal clade Ostentoria. A smaller deletion of 237-246bp was diagnostic of the superordinal clade Afrotheria.
Mol Phylogenet Evol 2003 Aug
PMID:A new phylogenetic marker, apolipoprotein B, provides compelling evidence for eutherian relationships. 1287 60

We sequenced the complete mitochondrial (mt) genomes of three insectivores: the long-eared hedgehog Hemiechinus auritus, the Japanese mole Mogera wogura, and the greater Japanese shrew-mole Urotrichus talpoides. These mtDNA data together with other previously sequenced mtDNAs were analyzed using a maximum likelihood method to infer their phylogenetic relationships among eutherians. Previous mitochondrial protein analyses used a simple model that did not consider site-heterogeneity, and Erinaceoidea (hedgehogs and moonrats) was placed at the basal eutherian position that is separated from Soricoidea (shrews) and Talpoidea (moles), suggesting the exclusion of the Erinaceoidea-Eulipotyphla tree. By including the new mtDNA sequences and introducing site-heterogeneity into the model, the Erinaceoidea-Eulipotyphla tree emerges as the best tree or as a tree with a log-likelihood score indistinguishable from that of the best tree. However, this conclusion depends on species sampling in Erinaceoidea, demonstrating the importance of both species sampling and use of an appropriate substitution model when inferring phylogenetic relationships.
Mol Phylogenet Evol 2003 Aug
PMID:Mitochondrial phylogeny of hedgehogs and monophyly of Eulipotyphla. 1287 64

The gastrointestinal tract develops from a simple tube to a complex organ with patterns of differentiation along four axes of asymmetry. The organ is composed of all three germ layers signaling to each other during development to form the adult structure. The gut epithelium is a constitutively developing tissue, constantly differentiating from a stem cell in a progenitor pool throughout the life of the organism. Signals from the adjacent mesoderm and between epithelial cells are required for normal orderly development/differentiation, homeostasis, and apoptosis. Embryonically important patterning factors are used during adult stages for these processes. Such critical pathways as the hedgehog, bone morphogenetic protein, Notch, Sox, and Wnt systems are used both in embryologic and adult times of gut development. We focus on and review the roles of these factors in gut epithelial cell development and differentiation.
Cell Mol Life Sci 2003 Jul
PMID:Development and differentiation of the intestinal epithelium. 1294 21

Loss of limb skeletal elements is a recurring theme in tetrapod evolution, but the developmental mechanisms underlying this phenomenon remain largely unknown. The Australian lizard genus Hemiergis offers an excellent model system to study limb reduction among closely related, naturally occurring populations with different numbers of digits. Evolutionary digit loss in Hemiergis does not result from simple truncation of a pentadactyl skeletal developmental program. Rather, the duration of embryonic expression of the patterning molecule Sonic hedgehog (SHH) is shortened in limbs with reduced numbers of digits, and is correlated with decreased cell proliferation in the posterior aspect of the limb. Moreover, this comparative analysis suggests an early role for SHH in specification of digit identity and later importance in maintaining cell proliferation and survival. Subtle changes in spatial or temporal regulation of SHH may alter proliferation and patterning of the developing limb, thereby effecting divergence in adult limb morphology among closely related species. In contrast, expression of MSX and Distal-less proteins were similar among embryos from different populations.
J Exp Zool B Mol Dev Evol 2003 Jun 15
PMID:Developmental basis of evolutionary digit loss in the Australian lizard Hemiergis. 1295 43

Hedgehog interacting protein (Hip) is considered as a membrane protein implicated in sequestering the hedgehog (hh) morphogens during embryonic development. Here, we demonstrate that Hip transcription also occurs in cells scattered in discrete brain areas of adult rodents and we identify the presence of membrane-associated and soluble forms of Hip in the mature brain. Moreover, we show that soluble forms of Hip, present in the conditioned medium of HEK293 cells overexpressing Hip, inhibit Sonic hedgehog (Shh)-induced differentiation of C3H10T1/2 cells, a well-characterised response associated with Shh signalling. After transfection in HEK293 cells, Hip partitions with the raft component ganglioside GM1 during density gradient centrifugation. Analysis of tagged Hip constructs reveals that the putative transmembrane domain of Hip is not cleaved suggesting that other mechanisms are implicated in the release of its soluble forms. Taken together, these data are consistent with the involvement of both membrane-associated and soluble Hip in the regulation of Shh signalling in adult neural tissues.
Mol Cell Neurosci 2004 Feb
PMID:Hedgehog interacting protein in the mature brain: membrane-associated and soluble forms. 1501 48

The Zic family of zinc-finger proteins plays a crucial role in neural development. Zic genes are vertebrate homologs of odd-paired, the Drosophila pair-rule gene. Their gene products have zinc-finger domains similar to those of Gli proteins, which act as transcriptional regulators in hedgehog signaling. Recent studies of human, mouse, frog, fish and ascidian Zic homologs have provided evidence that Zic genes are involved in a variety of developmental processes, including neurogenesis, myogenesis, skeletal patterning, and left-right axis establishment. Zic genes appear to have multiple roles in neural development. They control the initial phase during which ectoderm differentiates into neuroectoderm, and they may act as bridges between secreted neural tissue induction signals and the basic-helix-loop-helix class of neurogenesis-inducing transcriptional regulatory factors. Studies of loss-of-function mutations with differing Zic gene subtypes show that the Zic family of genes controls the process of neurulation. Mutations result in neural tube defects, which are seen at different rostrocaudal levels depending on which Zic gene subtype has been affected. Development of holoprosencephaly, forebrain anomalies, and cerebellar dysgenesis indicate that region-specific morphogenesis of the CNS is also controlled by Zic genes. The underlying molecular actions of Zic gene products, which allow them to control development, remain a mystery. Recent molecular characterization has shown that Zic proteins are able to bind Gli-binding DNA sequences in a sequence-specific manner, but with lower affinity than Gli proteins. Zic proteins also can activate transcription from several promoters. Furthermore, Zic and Gli proteins interact physically via their zinc-finger domains, raising the possibility that Zic proteins can act as transcriptional cofactors and modulate the hedgehog-signaling pathway. Clarification of the specific cooperating factors is therefore required in each case. Other evidence also suggests that Zic proteins can inhibit neuronal differentiation by activating Notch signals. This association might be is a clue toward understanding of the multifunctional property of Zic proteins because Notch signaling also is implicated in the control of several developmental processes.
Mol Cell Neurosci 2004 Jun
PMID:The role of Zic genes in neural development. 1520 46


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