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Hochschulschrift

Analysis of the expression pattern and knock-out phenotype of Slit-like 2 (Slitl2) in the mouse.

MPG-Autoren

Mayer,  Michaela
Max Planck Society;

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Mayer_Dissertation.pdf
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Zitation

Mayer, M. (2010). Analysis of the expression pattern and knock-out phenotype of Slit-like 2 (Slitl2) in the mouse. PhD Thesis, Freie Universität Berlin, Berlin.


Zitierlink: http://hdl.handle.net/11858/00-001M-0000-0010-7BD3-B
Zusammenfassung
The murine Slit-like 2 (Slitl2) gene was first identified in 2002, and so far, no reports have been published on it. This thesis aimed at answering two basic questions when first analyzing the function of a gene: a) Where is the gene expressed? and b) What happens if the gene function is abolished? A comprehensive temporospatial expression pattern was provided by describing not only endogenous Slitl2 expression, but also reporter gene expression in Slitl2- LacZ knock-in and in Slitl2-Venus transgenic mice. All three approaches rendered consistent results and revealed widespread expression from early developmental stages onwards. Prominent expression was observed in the developing as well as the adult skeletal system. Likewise, vascular smooth muscle cells and glomeruli exhibited strong expression throughout all stages of development. Moderate expression was, for example, seen in the adult lung epithelium and pancreatic islets of Langerhans. Collectively, the findings from the expression analysis indicated important roles for Slitl2 in the mouse. Non-redundant functions of Slitl2 could indeed be demonstrated by the generation of Slitl2-deficient mice via classical gene targeting in embryonic stem cells. Slitl2-mutant mice are phenotypically indistinguishable from their wild-type littermates at birth but develop a progressive illness and succumb to renal failure by 3-4 weeks of age. Prenatal kidney development appears unimpaired, and defects only emerge after birth. Renal insufficiency in these mice is characterized by severe glomerular lesions with massive podocyte effacement, capillary ectasia or even complete atrophy of the capillary tufts. Slitl2-deficient mice develop nephrotic syndrome with massive proteinuria and severe hypalbuminemia, which ultimately causes hyaline droplet nephropathy as well as subcutaneous edema, hydrothorax, and ascites. In addition, moribund null mutants are uremic, which further reflects renal failure in these animals. Despite the fact that kidney failure inevitably entails a perturbed bone metabolism, the decreased bone density in conjunction with a low bone turnover in Slitl2-deficient mice could also be a direct cause of the gene inactivation with regard to the distinct expression of Slitl2 in the skeletal system already at embryonic stages. The marked splenic and thymic atrophy in moribund Slitl2-deficient mice, on the other hand, could be attributed to increased serum levels of corticosterone and are therefore considered to be secondary effects. This thesis has laid the groundwork for future studies which will have to address the exact mechanism of the glomerular defects of the Slitl2 mutants and elucidate the underlying signaling pathway. With millions of people affected with kidney disease, this mouse model may serve as a valuable tool for in vivo studies and for testing potential therapeutic modalities.