Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.2.1.23 (beta-galactosidase)
14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The HOX11 homeobox gene was identified via the translocation t(10;14) in T cell leukaemia. To determine the function of this gene in mice, null mutations were made using homologous recombination in ES cells to incorporate lacZ into the hox11 transcription unit. Production of beta-galactosidase from the recombinant hox11 allele in +/- mutants allowed identification of sites of hox11 expression which included the developing spleen. Newborn hox11 -/- mice exhibit asplenia. Spleen formation commences normally at E11.5 in hox11 -/- mutant embryos but the spleen anlage undergoes rapid and complete resorption between E12.5 and E13.5. Dying spleen cells exhibit molecular features of apoptosis, suggesting that programmed cell death is initiated at this stage of organ development in the absence of hox11 protein. Thus hox11 is not required to initiate spleen development but is essential for the survival of splenic precursors during organogenesis. This function for hox11 suggests that enhanced cell survival may result from the t(10;14) which activates HOX11 in T cell leukaemias, further strengthening the association between oncogene-induced cell survival and tumorigenesis.
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PMID:The Hox11 gene is essential for cell survival during spleen development. 755 17

The Zfy-1 and Zfy-2 genes, which arose by gene duplication, map to the mouse Y chromosome and encode nearly identical zinc-finger proteins. Zfy-1 is expressed in the genital ridge and adult testis and likely encodes a transcription activator. Although potential roles in sex determination and spermatogenesis have been hotly debated, the biological functions of Zfy-1 remain unknown. To study the gene's regulation, transgenes with 21-28 kb of Zfy-1 5' flanking DNA placed upstream of lacZ were constructed in plasmids or created by homologous recombination of coinjected DNA molecules. The resulting transgenic mice expressed beta-galactosidase in the genital ridge of both males and females starting between embryonic day 10 and 11 (E10-E11), peaking at E12-E13 and then declining to low levels by E15, a pattern that matches Zfy-1 mRNA as detected by RT-PCR. This lacZ expression in genital ridge was confined to somatic cells as demonstrated by its absence from the alkaline phosphatase-positive germ cells. It had been reported previously that Zfy-1 mRNA was absent from the embryonic gonad of homozygous W(e) embryos, which virtually lack germ cells. By contrast, we observed normal expression of the Zfy-1/lacZ transgene when introduced into the W(e) background, suggesting that germ cells are not necessary for expression. In the adult, the Zfy-1/lacZ transgene is expressed abundantly in developing germ cells. Extragonadal (kidney, meninges, arteries, choroid plexus) expression of the transgene was also observed in embryos. A smaller transgene with only 4.3 kb of Zfy-1 5' flanking DNA was expressed only in germ cells of adult mice. These results suggest that an enhancer for germ cell expression in the adult lies near the Zfy-1 promoter and that an enhancer for expression in the somatic cells of the embryonic gonad is located further 5'.
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PMID:Expression of a mouse Zfy-1/lacZ transgene in the somatic cells of the embryonic gonad and germ cells of the adult testis. 805 Mar 62

A method of cell labelling based on homologous recombination has been developed to analyze the lineage of cells in intact embryos. In this method a LacZ gene bearing an inactivating duplication in its coding frame (termed LaacZ gene) is inserted into the genome of mice. Subsequently, in transgenic embryos, homologous recombination within the duplication recreates an open reading frame for beta-galactosidase. The descendants of the modified cell are identified histochemically. This recombination occurs at random and with low frequency. It can occur in cells in which the gene is not transcribed. It can also be intragenic (in adjacent sequences) as single transgene copies are found to recombine. To analyze the lineage of cells in the myotome the expression of the LaacZ gene is driven by a promoter which confers expression specifically to cells of this compartment. The analysis in 40-somite embryos (E11.5) is reported. We show that individual beta-gal+ myotomal clones may contribute to somites from both sides of the animal, in which case the right and the left somites are labelled consecutively and at the same antero-posterior level. It reflects predictable clonal origin of myotomal cells at the primitive streak stage or before and demonstrates three morphogenetic movements in the mesoderm: bilateral, antero-posterior and mediolateral. The results also show that the left-right assignation of myotomal cells in mouse is late, probably occurring during cell migrations at gastrulation. It applies also to presumptive myotomal cells of limb musculature. These results contrast with early left-right assignation of most tissues in Xenopus and Zebrafish. Some clones contribute to distant somites, suggesting persistence of presumptive myotomal cells in the presumptive paraxial mesoderm and clonal organisation of the myotome.
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PMID:Clonal analysis in the intact mouse embryo by intragenic homologous recombination. 806 30

During development of the vertebrate nervous system, the neural cell adhesion molecule (N-CAM) is expressed in a defined spatiotemporal pattern. We have proposed that the expression of N-CAM is controlled, in part, by proteins encoded by homeobox genes. This hypothesis has been supported by previous in vitro experiments showing that products of homeobox genes can both bind to and transactivate the N-CAM promoter via two homeodomain binding sites, HBS-I and HBS-II. We have now tested the hypothesis that the N-CAM gene is a target of homeodomain proteins in vivo by using transgenic mice containing native and mutated N-CAM promoter constructs linked to a beta-galactosidase reporter gene. Segments of the 5' flanking region of the mouse N-CAM gene were sufficient to direct expression of the reporter gene in the central nervous system in a pattern consistent with that of the endogenous N-CAM gene. For example, at embryonic day (E) 11, beta-galactosidase staining was found in postmitotic neurons in dorsolateral and ventrolateral regions of the spinal cord; at E14.5, staining was seen in these neurons throughout the spinal cord. In contrast, mice carrying an N-CAM promoter-reporter construct with mutations in both homeodomain binding sites (HBS-I and HBS-II) showed altered expression patterns in the spinal cord. At E11, beta-galactosidase expression was seen in the ventrolateral spinal cord, but was absent in the dorsolateral areas, and at E 14.5, beta-galactosidase expression was no longer detected in any cells of the cord. Homeodomain binding sites found in the N-CAM promoter thus appear to be important in determining specific expression patterns of N-CAM along the dorsoventral axis in the developing spinal cord. These experiments suggest that the N-CAM gene is an in vivo target of homeobox gene products in vertebrates.
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PMID:Embryonic expression patterns of the neural cell adhesion molecule gene are regulated by homeodomain binding sites. 870 Aug 54

Mice lacking neurotrophin-3 (NT-3) have been shown previously to be born with severe sensory deficits. This study characterizes the developmental course of this deficit in the trigeminal sensory ganglion, which in NT-3 homozygous mutants contains only 35% of the normal number of neurons at birth. At embryonic day 10.5 (E10.5), normal numbers of neurons, as assessed by expression of neurofilament protein and of total cells, are present in the ganglia of mutant homozygotes. During the next 3 d (E10.5-E13.5), virtually all of the deficit develops, after which mutant animals retain only approximately 30% the normal number of neurons. Quantification of neuronal and neuronal precursor numbers in normal and mutant animals reveals that neurons are specifically depleted in the absence of NT-3. A deficiency in precursor proliferation is only seen after most of the neuronal deficit has developed. Numbers of apoptotic cells in the ganglia of mutant animals are elevated during this same interval, indicating that the neuronal deficit is caused, in large part, by increased cell death of embryonic neurons. To determine sources of NT-3 in the trigeminal system, we examined the expression pattern of beta-galactosidase in mice, in which lacZ has replaced the NT-3 coding exon. E10.5-E11.5 embryos exhibit intense reporter expression throughout the mesenchyme and epithelia of the first branchial arch. Beta-galactosidase expression in E13.5 embryos is largely confined to the oral epithelium and the mesenchyme underlying the skin. Throughout the E10.5-E13.5 interval, the trigeminal ganglion and its targets in the CNS do not express reporter activity. We conclude that NT-3 acts principally as a peripherally derived survival factor for early trigeminal neurons.
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PMID:Neurotrophin-3 is a survival factor in vivo for early mouse trigeminal neurons. 892 22

To address origins of glomerular endothelial and mesangial cells in embryonic mammalian kidneys, we established interspecies grafts between rats and mice, in which fetal kidneys were implanted into the anterior eye chamber of adult hosts. After 5-7 days, hosts bearing grafts received intravenous injections with species-specific monoclonal antibodies (MAbs) to matrix components. In all cases, glomerular basement membranes and mesangial matrices labeled solely for donor-derived matrix. Additionally, microvessel extracellular matrices within grafts were usually of donor origin. To examine directly the origin of glomerular endothelial and mesangial cells, we grafted embryonic gestational days 11-12 (E11-12) kidneys from normal mice into anterior eye chambers of host reverse-orientation splice acceptor 26 mice, which are transgenic animals that express beta-galactosidase in every cell. When grafts were developed for beta-galactosidase activity, host cells were seen in peripheral vessels, but the majority of glomerular endothelial cells were of donor, not host, origin. Where host-derived-endothelial cells were found in glomeruli, donor endothelial cells were present as well. Mesangial cells were always of donor origin. When E11 mouse kidneys were labeled with the endothelial cell-specific Bandeiraea simplicifolia isolectin B4, we determined that endothelial cells are present from the inception of metanephrogenesis. Together, the evidence shows that cells of endogenous kidney origin were almost entirely responsible for development of the glomerular microvasculature in oculo. External vessels from the host, although important for graft maintenance, were not major contributors to the glomerulus.
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PMID:Endogenous origin of glomerular endothelial and mesangial cells in grafts of embryonic kidneys. 892 52

The rat protease nexin-1 (PN-1) promoter contains a GCGGGGGCG binding site for the transcription factors Krox-24, Krox-20 and NGFI-C. Mutations of this site abolished binding of Krox-24 in vitro. The wildtype protease nexin-1 promoter expressed beta-galactosidase similarity to the expression of protease nexin-1 mRNA. When the function of this Krox site was tested in vivo using transgenic F0 embryos, mutation had two opposite effects. beta-Galactosidase expression increased in cartilage and heart at both stages E11.5 and E13.5, but was abolished in nerves of the central and peripheral nervous system at stage E13.5. These results suggest that Krox factors are among the important transcription factors regulating protease nexin-1 expression and thereby intracellular proteolytic activity in embryonic heart, cartilage and parts of the nervous system.
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PMID:A Krox binding site regulates protease nexin-1 promoter activity in embryonic heart, cartilage and parts of the nervous system. 902 67

The neural cell adhesion molecule (N-CAM) mediates cell-cell interactions and is expressed in characteristic spatiotemporal patterns during development. In previous studies of factors that control N-CAM gene expression, we identified a binding site for the paired domain of Pax proteins (designated PBS) in the mouse N-CAM promoter. In this study, we demonstrate that a transcription factor known to be important for development of the central nervous system, Pax-6, binds to the N-CAM PBS and show that the PBS can influence N-CAM expression in vivo. Pax-6, produced in COS-1 cells, bound to the PBS through two half-sites, PBS-1 and PBS-2; mutations in both of these sites completely disrupted binding. Moreover, nuclear extracts from embryonic day (E) 11.5 mouse embryos bound to the PBS, and this binding was inhibited by antibodies to Pax-6. To determine the role of the PBS in vivo, we generated transgenic mice with N-CAM promoter/lacZ gene constructs containing either a wild-type or a mutated PBS. Mutations in PBS-1 and PBS-2 decreased the extent of beta-galactosidase expression in the mantle layer of the spinal cord limiting it to ventral regions at E11.5. At E14.5, these mutations eliminated most of the expression that was seen in the wild-type spinal cord. Taken together with our previous observations that the PBS binds multiple Pax proteins, the data indicate that such binding contributes to the regulation of N-CAM gene expression during neural development.
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PMID:A binding site for Pax proteins regulates expression of the gene for the neural cell adhesion molecule in the embryonic spinal cord. 903 76

Flk1, a receptor tyrosine kinase for vascular endothelial growth factor (VEGF), is the earliest known marker for endothelial precursors (angioblasts). We examined heterozygous mice in which the Flk1 gene was partially replaced by a promoter-less LacZ insert and used beta-galactosidase histochemistry to view cells transcribing Flk1. In day 10 (E10) embryos, a Flk1-positive network surrounded the metanephric blastema, and, at E11, a vessel entered the metanephros from its ventral aspect alongside the ingrowing ureteric bud. However, aortic branches did not engage embryonic kidneys at these time points. In newborns, beta-galactosidase was localized exclusively and intensely to endothelial cells of all vessels and glomeruli. In contrast, when E12 kidneys grown in organ culture for 6 days were examined, only scattered Flk1-positive cells were seen, glomeruli were unlabeled, and vessels were absent. When organ-cultured kidneys were then grafted into wild-type anterior eye chambers, numerous Flk1-positive endothelial cells in vessels and glomeruli were found, all stemming from the graft. Image analysis showed that grafts with the most abundant glomerulo- and tubulogenesis were also those with the richest expression of Flk1. We conclude that 1) kidney microvessels precede renal artery development, 2) angioblast differentiation is arrested in organ culture but released on grafting when vasculogenesis resumes, and 3) nephrogenesis and microvessel assembly are tightly coupled in vivo.
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PMID:Direct visualization of renal vascular morphogenesis in Flk1 heterozygous mutant mice. 968 18

Transforming growth factor-beta(1) (TGF-beta(1)) is expressed in the adult and embryonic vasculature; however, the biological consequences of increased vascular TGF-beta(1) expression remain controversial. To establish an experimental setting for investigating the role of increased TGF-beta(1) in vascular development and disease, we generated transgenic mice in which a cDNA encoding a constitutively active form of TGF-beta(1) is expressed from the SM22alpha promoter. This promoter fragment directs transgene expression to smooth muscle cells of large arteries in late-term embryos and postnatal mice. We confirmed the anticipated pattern of SM22alpha-directed transgene expression (heart, somites, and vasculature of the embryo and yolk sac) in embryos carrying an SM22alpha-beta-galactosidase transgene. SM22alpha- beta-galactosidase transgenic mice were born at the expected frequency (13%); however, nearly all SM22alpha-TGF-beta(1) transgenic mice died before E11.5. SM22alpha-TGF-beta(1) transgenic embryos identified at E8.5 to E10.5 had growth retardation and both gross and microscopic abnormalities of the yolk sac vasculature. Overexpression of TGF-beta(1) from the SM22alpha promoter is lethal at E8.5 to E10.5, most likely because of yolk sac insufficiency. Investigation of the consequences of increased vascular TGF-beta(1) expression in adults may require a conditional transgenic approach. Moreover, because the SM22alpha promoter drives transgene expression in the yolk sac vasculature at a time when embryonic survival is dependent on yolk sac function, use of the SM22alpha promoter to drive expression of "vasculoactive" transgenes may be particularly likely to cause embryonic death.
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PMID:Cardiovascular overexpression of transforming growth factor-beta(1) causes abnormal yolk sac vasculogenesis and early embryonic death. 1082 31


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