Home About us Contact
|
Home About us Contact | ||
|
|
||
Conditional Inactivation (conditional + inactivation)
Selected AbstractsConditional gene inactivation reveals roles for Fgf10 and Fgfr2 in establishing a normal pattern of epithelial branching in the mouse lungDEVELOPMENTAL DYNAMICS, Issue 8 2009Lisa L. Abler Abstract Fibroblast growth factor 10 (FGF10) signaling through FGF receptor 2 (FGFR2) is required for lung initiation. While studies indicate that Fgf10 and Fgfr2 are also important at later stages of lung development, their roles in early branching events remain unclear. We addressed this question through conditional inactivation of both genes in mouse subsequent to lung initiation. Inactivation of Fgf10 in lung mesenchyme resulted in smaller lobes with a reduced number of branches. Inactivation of Fgfr2 in lung epithelium resulted in disruption of lobes and small epithelial outgrowths that arose arbitrarily along the main bronchi. In both mutants, there was an increase in cell death. Also, the expression patterns of key signaling molecules implicated in branching morphogenesis were altered and a proximal lung marker was expanded distally. Our results indicate that both Fgf10 and Fgfr2 are required for a normal branching program and for proper proximal,distal patterning of the lung.Developmental Dynamics 238:1999,2013, 2009. © 2009 Wiley-Liss, Inc. [source] Endothelium-specific Cre recombinase activity in flk-1-Cre transgenic miceDEVELOPMENTAL DYNAMICS, Issue 2 2004Alexander H. Licht Abstract The use of the Cre-loxP recombination system allows the conditional inactivation of genes in mice. The availability of transgenic mice in which the Cre recombinase expression is highly cell type specific is a prerequisite to successfully use this system. We previously have characterized regulatory regions of the mouse flk-1 gene sufficient for endothelial cell-specific expression of the LacZ reporter gene in transgenic mice. These regions were fused to the Cre recombinase gene, and transgenic mouse lines were generated. In the resulting flk-1-Cre transgenic mice, specificity of Cre activity was determined by cross-breeding with the reporter mouse lines Rosa26R or CAG-CAT-LacZ. We examined double-transgenic mice at different stages of embryonic development (E9.5,E16.5) and organs of adult animals by LacZ staining. Strong endothelium-specific staining of most vascular beds was observed in embryos older than E11.5 in one or E13.5 in a second line. In addition, the neovasculature of experimental BFS-1 tumors expressed the transgene. These lines will be valuable for the conditional inactivation of floxed target genes in endothelial cells of the embryonic vascular system. Developmental Dynamics 229:312,318, 2004. © 2004 Wiley-Liss, Inc. [source] Floxed allele for conditional inactivation of the GABAB(1) geneGENESIS: THE JOURNAL OF GENETICS AND DEVELOPMENT, Issue 3 2004Corinne Haller Abstract GABAB receptors are the G-protein-coupled receptors for the neurotransmitter GABA. GABAB receptors are broadly expressed in the nervous system. Their complete absence in mice causes premature lethality or,when mice are viable,epilepsy, impaired memory, hyperalgesia, hypothermia, and hyperactivity. A spatially and temporally restricted loss of GABAB function would allow addressing how the absence of GABAB receptors leads to these diverse phenotypes. To permit a conditional gene inactivation, we flanked critical exons of the GABAB(1) gene with lox511 sites. GABAB(1)lox511/lox511 mice exhibit normal levels of GABAB(1) protein, are fertile, and do not display any behavioral phenotype. We crossed GABAB(1)lox511/lox511 with Cre-deleter mice to produce mice with an unrestricted GABAB receptor elimination. These GABAB(1),/, mice no longer synthesize GABAB(1) protein and exhibit the expected behavioral abnormalities. The conditional GABAB(1) allele described here is therefore suitable for generating mice with a site- and time-specific loss of GABAB function. genesis 40:125,130, 2004. © 2004 Wiley-Liss, Inc. [source] Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complexANNALS OF NEUROLOGY, Issue 4 2008Ling-Hui Zeng MD Objective Tuberous sclerosis complex (TSC) represents one of the most common genetic causes of epilepsy. TSC gene inactivation leads to hyperactivation of the mammalian target of rapamycin signaling pathway, raising the intriguing possibility that mammalian target of rapamycin inhibitors might be effective in preventing or treating epilepsy in patients with TSC. Mice with conditional inactivation of the Tsc1 gene primarily in glia (Tsc1GFAPCKO mice) develop glial proliferation, progressive epilepsy, and premature death. Here, we tested whether rapamycin could prevent or reverse epilepsy, as well as other cellular and molecular brain abnormalities in Tsc1GFAPCKO mice. Methods Tsc1GFAPCKO mice and littermate control animals were treated with rapamycin or vehicle starting at postnatal day 14 (early treatment) or 6 weeks of age (late treatment), corresponding to times before and after onset of neurological abnormalities in Tsc1GFAPCKO mice. Mice were monitored for seizures by serial video-electroencephalogram and for long-term survival. Brains were examined histologically for astrogliosis and neuronal organization. Expression of phospho-S6 and other molecular markers correlating with epileptogenesis was measured by Western blotting. Results Early treatment with rapamycin prevented the development of epilepsy and premature death observed in vehicle-treated Tsc1GFAPCKO mice. Late treatment with rapamycin suppressed seizures and prolonged survival in Tsc1GFAPCKO mice that had already developed epilepsy. Correspondingly, rapamycin inhibited the abnormal activation of the mammalian target of rapamycin pathway, astrogliosis, and neuronal disorganization, and increased brain size in Tsc1GFAPCKO mice. Interpretation Rapamycin has strong efficacy for preventing seizures and prolonging survival in Tsc1GFAPCKO mice. Ann Neurol 2008 [source] | ||||||||||