Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.23 (beta-galactosidase)
 14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Skeletal muscles in the vertebrate body are derived from the somites, epithelial spheres of cells which segment from the paraxial mesoderm in a rostral-caudal developmental gradient on either side of the neural tube. Initially, cells in the somite are multipotent and their fate depends on the environmental influences exerted by neighbouring tissues, notably the axial structures (neural tube and notochord), and the dorsal ectoderm. The ventralizing influence exerted by the notochord and floor plate of the neural tube through the action of sonic hedgehog, results in the differentiation of sclerotome which will give rise to cartilage and bone of the vertebral column and ribs. The dorsal derivatives of the somite, formed from cells in the dermomyotome, are derm and skeletal muscle. The onset of skeletal myogenesis is characterized by expression of myogenic factors, notably myf-5 and MyoD, members of the superfamily of helix-loop-helix transcription factors. Another member of the myogenic factor family, myogenin, is subsequently expressed and leads to muscle cell differentiation with activation of the downstream muscle-specific genes. Dorsalization of the somite and subsequent myogenesis depends on the presence of axial structures and dorsal ectoderm. The Wnt family of signalling molecules are potentially implicated in this process. Muscle progenitor cells present in the medial part of the dermomyotome activate myf-5 first and explant experiments have shown that the axial structures lead to the activation of this myogenic factor and subsequent myogenesis which results in the formation of the dorsal myotome in the central region of the somite. This contributes to the formation of axial muscles. Muscle progenitor cells in the lateral part of the dermomyotome preferentially activate MyoD and this depends on the presence of dorsal ectoderm. These cells will form the ventral aspect of the myotome, and later contribute to body wall muscles, for example. Part of the lateral progenitor population migrates away from the somite to form peripheral body muscles and the muscles of the limb. In this case myogenic factors are not initially expressed and these migratory cells are characterized by the expression of the paired-box gene Pax3. In explant experiments lateral mesoderm retards the induction of MyoD expression by dorsal ectoderm; in vivo this may be important to permit cell migration prior to differentiation. In mice carrying mutations in both MyoD and myf-5 no skeletal muscle forms, whereas myogenesis can take place in the absence of either MyoD or myf-5. Normally, cells in which one gene is activated first, subsequently co-express the other, so that there rapidly cease to be distinct MyoD+ or myf-5+ populations in the embryo. In myf-5-/- mice no myotome forms initially, but MyoD is subsequently activated. This takes place medially, as well as laterally, under the influence of the more mature neural tube and notochord. By targetting the myf-5 gene with an nlacZ reporter gene it has been possible to follow the fate of the early muscle progenitor cell population in which the myf-5 gene has been activated but no myf-5 protein is present. These beta-galactosidase positive cells delaminate from the dermomyotome, but instead of migrating under this epithelium to form the myotome, they migrate aberrantly. Some cells localize dorsally under the epiderm and begin to express the dermal marker, Dermo-1. Other muscle progenitor cells migrate ventrally into the sclerotomal compartment where they express an early sclerotomal marker, scleraxis. Later in the mutant mice, when cells from this compartment have condensed to form the cartilage of the ribs, beta-galactosidase positive cells are detectable within the ribs. These observations indicate that the early myogenic factor myf-5 is necessary to ensure the correct positioning of myogenic progenitor cells within the embryo. (ABSTRACT TRUNCATED)
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PMID:[Early stages of myogenesis as seen through the action of the myf-5 gene]. 918 Nov 27

In most instances of preaxial polydactyly (PPD), Sonic Hedgehog (Shh), an essential limb patterning signal, is ectopically expressed in an anterior region of the developing limb in addition to the normal posterior domain. It is thought that this anterior Shh expression leads directly to the development of the extra digits. Recent reports have identified a conserved limb-specific Shh enhancer approximately 1 megabase upstream of the Shh transcription initiation site, and individual base pair changes within this region are associated with PPD. We report here that a single base pair change within this enhancer is sufficient to drive beta-galactosidase expression in both anterior and posterior limb domains, similar to Shh expression in animal PPD models, whereas a wild-type construct is expressed only in the posterior limb, similar to Shh expression in normal embryos. These findings provide the first direct evidence that a single base pair change within the limb-specific Shh enhancer acts as a genetic basis for PPD.
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PMID:Single base pair change in the long-range Sonic hedgehog limb-specific enhancer is a genetic basis for preaxial polydactyly. 1563 98

The zinc-finger transcription factor GLI3 acts during vertebrate development in a combinatorial, context-dependent fashion as a primary transducer of sonic hedgehog (SHH) signaling. In humans, mutations affecting this key regulator of development are associated with GLI3-morphopathies, a group of congenital malformations in which forebrain and limb development are preferentially affected. We show that a non-coding element from intron two of GLI3, ultraconserved in mammals and highly conserved in the pufferfish Fugu, is a transcriptional enhancer. In transient transfection assays, it activates reporter gene transcription in human cell cultures expressing endogenous GLI3 but not in GLI3 negative cells. The identified enhancer element is predicted to contain conserved binding sites for transcription factors crucial for developmental steps in which GLI3 is involved. The regulatory potential of this element is conserved and was used to direct tissue-specific expression of a green fluorescent protein reporter gene in zebrafish embryos and of a beta-galactosidase reporter in transgenic mouse embryos. Time, location, and quantity of reporter gene expression are congruent with part of the pattern previously reported for endogenous GLI3 transcription.
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PMID:Ultraconserved non-coding sequence element controls a subset of spatiotemporal GLI3 expression. 1766 44

Gli signaling is critical for central nervous system development and is implicated in tumorigenesis. To monitor Gli signaling in gliomas in vivo, we created platelet-derived growth factor-induced gliomas in a Gli-luciferase reporter mouse. We find that Gli activation is found in gliomas and correlates with grade. In addition, we find that sonic hedgehog (SHH) is expressed in these tumors and also correlates with grade. We identify microvascular proliferation and pseudopalisades, elements that define high-grade gliomas as SHH-producing microenvironments. We describe two populations of SHH-producing stromal cells that reside in perivascular niche (PVN), namely low-cycling astrocytes and endothelial cells. Using the Ptc-LacZ knock-in mouse as a second Gli responsive reporter, we show beta-galactosidase activity in the PVN and in some tumors diffusely throughout the tumor. Lastly, we observe that SHH is similarly expressed in human gliomas and note that an intact tumor microenvironment or neurosphere conditions in vitro are required for Gli activity.
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PMID:Gli activity correlates with tumor grade in platelet-derived growth factor-induced gliomas. 1838 30

Cells localized in the bronchioalveolar duct junction of the murine lung have been identified as potential bronchioalveolar stem cells. Based on the surface marker expression, two main phenotypes have been proposed: Sca-1(+), CD34(+), CD45(-), Pecam(-) and Sca-1(low), CD34(-) CD45(-), Pecam(-) cells. An increase in the number of Sca-1(+), CD34(+) CD45(-), Pecam(-) cells and activation of the sonic hedgehog (Shh) pathway was observed following unilateral pneumonectomy and naphthalene-induced airway injury. Overexpression of Shh in the respiratory tract also resulted in an increase of this cell population. Syngeneic transplantation of beta-galactosidase-expressing bone marrow cells demonstrated that the increase of Sca-1(+), CD34(+), CD45(-), Pecam(-) cells in the lung was a result of local proliferation. Intratracheal administration of purified Shh-stimulated Sca-1(+), CD45(-), Pecam(-) cells coexpressing CD34 to syngeneic mice following pneumonectomy resulted in engraftment of these cells predominantly in the airways for up to 3 months, whereas Sca-1(-), CD45(-), Pecam(-) cells did not engraft. This study suggests that local Sca-1(+), CD34(+), CD45(-), Pecam(-) cells are stimulated during compensatory lung growth, following airway injury and overexpression of Shh and have some potential to engraft in the airways, without showing clonal properties in vivo.
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PMID:Overexpression of sonic Hedgehog in the lung mimics the effect of lung injury and compensatory lung growth on pulmonary Sca-1 and CD34 positive cells. 1986 52

Rationale: Irreversible hypofunction of salivary glands or xerostomia is common in head and neck cancer survivors treated with radiotherapy even when various new techniques are applied to minimize the irradiation (IR) damage. This condition severely impairs the quality of life of patients and can only be temporarily relieved with current treatments. We found recently that transient expression of Sonic Hedgehog (Shh) in salivary glands after IR rescued salivary function, but the underlying mechanisms are not totally clear. Methods: We generated a mouse model of IR-induced hyposalivation, and delivered adenoviral vectors carrying Shh or control GFP gene into submandibular glands (SMGs) via retrograde ductal instillation 3 days after IR. The cellular senescence was evaluated by senescence-associated beta-galactosidase assay and the expression of senescence markers. The underlying mechanisms were explored by examining DNA damage, oxidative stress, and the expression of related genes by qRT-PCR, Western blot and immunofluorescent staining. Results: Shh gene transfer repressed IR-induced cellular senescence by promoting DNA repair and decreasing oxidative stress, which is mediated through upregulating expression of genes related to DNA repair such as survivin and miR-21 and repressing expression of pro-senescence gene Gdf15 likely downstream of miR-21. Conclusion: Repressing cellular senescence contributes to the rescue of IR-induced hyposalivation by transient activation of Hh signaling, which is related to enhanced DNA repair and decreased oxidative stress in SMGs.
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PMID:Delivery of Sonic Hedgehog Gene Repressed Irradiation-induced Cellular Senescence in Salivary Glands by Promoting DNA Repair and Reducing Oxidative Stress. 2946 6