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Published April 18, 2006 | Published
Journal Article Open

Impaired neurogenesis and cardiovascular development in mice lacking the E3 ubiquitin ligases UBR1 and UBR2 of the N-end rule pathway


The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. A subset of degradation signals recognized by the N-end rule pathway comprises the signals, called N-degrons, whose determinants include destabilizing N-terminal residues. Our previous work identified a family of at least four mammalian E3 ubiquitin ligases, including UBR1 and UBR2, that share the UBR box and recognize N-degrons. These E3 enzymes mediate the multifunctional N-end rule pathway, but their individual roles are just beginning to emerge. Mutations of UBR1 in humans are the cause of Johanson–Blizzard syndrome. UBR1 and UBR2 are 46% identical and appear to be indistinguishable in their recognition of N-degrons. UBR1–/– mice are viable but have defects that include pancreatic insufficiency, similarly to UBR1–/– human patients with Johanson–Blizzard syndrome. UBR2–/– mice are inviable in some strain backgrounds and are defective in male meiosis. To examine functional relationships between UBR1 and UBR2, we constructed mouse strains lacking both of these E3s. We report here that UBR1–/–UBR2–/– embryos die at midgestation, with defects in neurogenesis and cardiovascular development. These defects included reduced proliferation as well as precocious migration and differentiation of neural progenitor cells. The expression of regulators such as D-type cyclins and Notch1 was also altered in UBR1–/–UBR2–/– embryos. We conclude that the functions of UBR1 and UBR2 are significantly divergent, in part because of differences in their expression patterns and possibly also because of differences in their recognition of protein substrates that contain degradation signals other than N-degrons.

Additional Information

©2006 by The National Academy of Sciences of the USA. Contributed by Alexander Varshavsky, March 2, 2006. Published online before print April 10, 2006, 10.1073/pnas.0601700103. We thank Raphael Kopan (Washington University, St. Louis) for advice about Notch-related experiments, Xiaochun Yu (Mayo Clinic, Rochester, MN) for staging mitotic cells, and Heather Buresch and Zhen Lu (University of Pittsburgh) for care of mice. This work was supported by National Institutes of Health Grants GM069482, GM074000 (to Y.T.K.), GM31530, and DK39520 (to A.V.); the American Heart Association (Y.T.K.); and the Ellison Medical Foundation (A.V.). Author contributions: J.Y.A., T.T., A.V., and Y.T.K. designed research; J.Y.A., J.W.S., T.T., M.J.L., and Y.T.K. performed research; J.Y.A. and Y.T.K. contributed new reagents/analytic tools; J.Y.A., J.W.S., T.T., M.J.L., A.V., and Y.T.K. analyzed data; and J.Y.A., A.V., and Y.T.K. wrote the paper. Conflict of interest statement: No conflicts declared.

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