Genetic Study of Pigment Granule Transport in the Mouse

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The dilute (d), ashen (ash), and leaden (ln) coat color mutations provide a unique model system for the study of vesicle transport in mammals. All three mutant loci encode genes that are required for the polarized transport of melanosomes, the specialized, pigment-containing organelles of melanocytes, to the neighboring keratinocytes and eventually into coat hairs. Furthermore, all three mutations are suppressed by a fourth mutation, dilute suppressor (dsu). Genetic studies suggest that d, ln, and ash function in the same or overlapping pathways and are supported by biochemical studies showing that d encodes an actin-based melanosome transport motor, MyoVA. We have also shown that ash encodes Rab27a, a small GTP-binding protein previously implicated in vesicle transport. In collaboration with John Hammer's laboratory, we demonstrated that Rab27a localizes to melanosomes and provided evidence suggesting that Rab27a serves as the MyoVA receptor on melanosomes. Subsequently, a number of investigators have confirmed our predictions and showed that Rab27a attachment to the melanosome is required for the recruitment of MyoVA into the transport complex. Myo5a and Rab27a are also mutated in human disease. Patients with a rare autosomal recessive disorder, Griscelli Syndrome, display hypopigmentation of the skin and hair. Some patients also display neurological impairment, which correlates with mutations in MYO5A; others show immune disorders in addition to the pigmentation alterations and this phenotype correlates with mutations in RAB27A. Very recently, we cloned the ln mutation based on its position on mouse chromosome 1. Interestingly, ln encodes a Rab effector that we have named melanophilin (Mlph). Ongoing work suggests that Mlph is a critical component of the melanosomal transport complex. Thus, as predicted by genetic studies, all three proteins appear to function as part of an integrated motor complex that is essential for vesicle transport in mammalian cells. Studies are also in progress to identify the product of dsu and to understand how the protein participates in directional vesicular transport.