International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany

Plenary Presentations * Oral Presentations *
Poster Presentations: Behavioural Genetics and Genomics * Development and Stem Cells * Functional Genome Analysis * Mouse Models of Human Disease * Mouse System Biology Bioinformatics * Multigenic and Multifactorial Trait Analysis * Nutrition and Metabolic Disease * Phenotyping Methods Imaging * The Genetics and Genomics of Infectious Disease *
Verne Chapman Memorial Lecture * Table of Contents * Sponsor/Exhibitor List * Awards * Photographs

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POSTER 17 - MIND BOMB 1 – AN E3 LIGASE IN THE NOTCH-DELTA SIGNALING PATHWAY ESSENTIAL FOR EMBRYONIC DEVELOPMENT

Rajendra R, Barsi J C
Departments of Pathology and Developmental Biology, Howard Hughes Medical Institute, Stanford University Medical School

Co-Authors: Wu J I, Artzt K
Institutions: Departments of Pathology and Developmental Biology, Howard Hughes Medical Institute, Stanford University Medical School

The Notch1-Delta1 signaling pathway is notably one of the most crucial during early embryonic development and is highly conserved. Regulation of Notch1 has been extensively studied. There are several Ubiquitin E3 ligases that play important roles in either activating Notch1 or for the turn over of different proteins in this pathway. Mind bomb (mib) is a Ubiquitin E3 ligase that, when mutated in zebrafish has been observed to over-produce neurons. Delta was shown to be a target for this E3 ligase (Itoh et al., 2003). Interestingly a biochemical approach revealed a second target of mib1, Death Associated Protein Kinase (DAPK) (Jin etal., 2002). To study the role of Mind bomb in mammals, a knockout of mib1 was generated in mouse.

Our analyses with mib1^-/- embryos indicate three major phenotypes at E9.5, abnormal somitogenesis, premature differentiation of the neuroepithelium and improper vasculature. Mib1^-/- mutants are embryonic lethal between E9.5 – E10. Our studies indicate that Delta (Dll1) transcript is misexpressed and the levels are lowered at E9.5 in the mib1^-/- embryos. We have also observed that the neuroepithelium in embryos fails to maintain an undifferentiated state and commits to the neural fate. Further, the absence of Hes5 transcript in mib1^-/- embryos was observed by RTPCR, indicative of premature Notch signaling. Our hypothesis is that, high levels of mis-expressed Delta results in the perturbation of the Notch-Delta signaling cascade. This in turn results in cells that have become neuroblasts, which then fail to regulate DAPK levels resulting in cell death.