International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


ORAL PRESENTATION

TUESDAY 11 NOVEMBER
12:30 – 12:45 HRS

UBIQUITINATION OF NOTCH PATHWAY DELTA LIGAND AND DEATH-ASSOCIATED PROTEIN KINASE IS ESSENTIAL TO MAINTAIN EMBRYONIC NEUROEPITHELIAL STEM CELLS

Barsi J C , Rajendra R
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 Notch-Delta signaling pathway controls many conserved cell determination events. While the Notch end is fairly well understood, the Delta end has been the dark side. Recent evidence indicates that Delta signaling is as complex as the Notch side; Delta (Dll1) is cleaved at least twice with an intracellular fragment transported to the nucleus presumably to affect downstream transcription factors. Delta can be ubiquitinated and endocytosed by neuralized (Neur). However, Neur is non-essential in mammals as the knockout is not lethal. Another RING finger E3 ligase responsible for ubiquitination of Delta is mindbomb (mib). When mutated in zebrafish, dramatic over production of early neurons is evident (Itoh et al 2003). A second target of mib was determined biochemically to be death associated protein kinase (DAPK) (Jin et al 2002).

We have analyzed the knockout of Mib1 in mouse. Mib1-/- embryos die at E10.5 and have the entire Notch-Delta pathway rendered non-functional. The consequences are: abnormal somites and angiogenesis, premature differentiation of the neuroepithelium with loss of polarity. Our studies have concentrated on the molecular analysis of the Mib1-/- nervous system. The phenotype is unique in the dramatic death of the premature newborn neurons. Our working hypothesis is that: with too much Dll1, the Notch pathway is disrupted and the cells differentiate en masse at E9.5. Thus, lateral inhibition is absent. With too much DAPK, apoptosis is deregulated and the differentiating neurons die. This could have implication for treating tumors and manipulating the differentiation of neural stem cells.


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