International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 20 - MIND BOMB1 – CHARACTERIZATION OF THE MIB1 KNOCKOUT IN MOUSE AND ITS ROLE IN THE NOTCH  SIGNALING PATHWAY

Rajendra R 1, Barsi JC 1, Wu JI 2, Artzt K 1

1 Department of Molecular Genetics & Microbiology, Institute of Cellular and Molecular Biology, University of Texas at Austin, Austin, United States, 2 Depatrments of Pathology and Developmental Biology, Howard Hughes Institute, Stanford Medical School, Palo Alto, United States

Early embryonic development is regulated by various signaling pathways, one of the most widely studied and conserved being the effect of Notch-Delta signaling. Experiments with Delta like1 (Dll1) have shown that, like Notch, it is cleaved twice resulting in an intracellular fragment, that is transported to the nucleus, to possibly affect transcriptional factors (Six et al.,2003). Dll1 protein is also ubiquitinated by two proteins Neuralized (Lai etal., 2001) and Mind bomb1 (Itoh et al., 2003). Neuralized is non-essential for embryogenesis, as the knockout is not lethal. On the other hand knockout of Mind bomb1 (mib1) results in embryonic lethality in both zebrafish and mice. Mib1 was also ascertained biochemically, to target the protein Death Associated Protein Kinase (DAPK) for ubiquitination (Jin etal., 2000).

We have generated a mib1 knockout in the mouse that results in embryonic lethality by day E10.5, which is preceeded by abnormal somitogenesis, improper vasculogenesis and premature neural differentiation.  We report here that the entire Notch1-Dll1 signaling pathway is disrupted and have focused mainly on the in vivo effects of the mib1 knock out pertaining to this pathway.The hypothesis based on our observations is that, failure to modulate Dll1 protein disrupts the signaling down-stream of Notch1, resulting in loss of lateral inhibition and premature differentiation into neuroblasts by E9.5. Further, the neuroblasts are unable to regulate DAPK levels in the absence of mib1, resulting in apoptosis. The mib1 knockout system is a useful tool in understanding neuronal differentiation with possible long-term implications for treating neural tumors.

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