International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


PLENARY PRESENTATION

monday 18 november

08:30 – 09:00 hrs

A MOLECULAR GENETIC APPROACH TO THE STUDY OF VESICLE TRANSPORT IN THE MOUSE

N Jenkins
National Cancer Institute

Co-Authors: 1) Matesic L, 1) Wilson S, 1) O’Sullivan T, 2) Huang J, 1) Yip R, 1) Swing D, 3) Russell L, 1) Copeland N
Institutions: 1) National Cancer Institute, 2) University of Hong Kong, 3) Oak Ridge National Laboratory

dilute (d), ashen (ash), and leaden (ln) are required for the polarized transport of melanosomes, the specialized, pigment-containing organelles of melanocytes, to the neighboring keratinocytes, and eventually, into coat hairs. Recent positional cloning and biochemical studies have shown that d encodes unconventional myosin-Va, an actin-based vesicle motor.  Myosin-Va binds its cargo, the melanosome, by interacting with a receptor-protein complex containing Rab27a (encoded by ash), and melanophilin (encoded by ln), a postulated Rab27a effector.  Rab27a binds to the melanosome first and then recruits melanophilin, which in turn recruits myosin-Va.  Binding of myosin-Va to Rab27A and melanophilin is dependent on exon F, an alternatively spliced exon in the myosin-Va tail.  Interestingly, the coat color defects observed in d, ash, and ln mice are suppressed by a loss-of-function mutation in a fourth gene, dilute suppressor (dsu).  dsu encodes a small protein with no known function or homology to proteins in current databases and may function in a new pathway that regulates vesicle transport in mammalian cells.  These studies provide the first description of an organelle receptor for an actin-based motor, further expand the functional repertoire of Rab GTPases and their effectors, illustrate how alternate exon usage can be used to specify cargo, and demonstrate the power of positional cloning for functionally annotating the mouse genome.


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