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Mammalian Development Laboratory

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  1. Genetic technologies in the mouse
  2. Molecular mechanisms of somite segmentation
  3. Germ cell development
  4. The roles of Notch signaling in cardiovascular development

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5. The roles of Notch signaling in cardiovascular development


The circulation system is the first to be established during embryogenesis in which cells derived from a part of the lateral plate mesoderm differentiate into cardiovascular tissues and form the complicated structures of the heart and blood vessels. Of interest to our laboratory and others are the specific factors that play a role in the development of these structures. A recent report has shown that Notch signaling plays a crucial role in both heart and vascular development (Fig. 1) whereby Notch1 and RBPJk mutants show collapse of the endocardium. Moreover, Jagged1 has been identified as a causative gene in Alagille syndrome and hence we are currently focusing on Notch signaling mechanisms in our studies of heart and blood vessel formation. We have previously cloned factors that are direct targets of the Notch signaling pathway, hairy and enhancer of split E(spl) genes (hesr1, hesr2 and hesr3), which encode bHLH transcriptional repressors, and have now generated a knockout mouse for each of these. Hesr2 single knockout mice die at around 10 days after birth and exhibit heart enlargement. These mutant mice also show hypomorphic AV valve formation and ventricular septal defects. We are currently analyzing the function of the hesr genes during cardiovascular development and can generate trans-heterozygous mice expressing desired genes in the cardiovascular system by crossing Mesp1-Cre mice (a Mesp1 locus Cre recombinase knockin) with CAG-lox-CAT-lox-genes (into which specific genes of interest can be inserted, e.g. Notch1 intracellular domain or hesr genes) (see Chapter 3 and Figure 2). Using this system, we can therefore conduct gain-of-function studies.





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