DISCUSSION 1

Myosin V : a motor protein involved in the regulation of dendrite formation and melanosome transport in the melanocyte?

Jo Lambert, Jean-Marie Naeyaert, Department of Dermatology,

University Hospital of Gent,

De Pintelaan 185, 9000 Gent, Belgium

Tel : 32-9-240.22.87/Fax : 32-9-240.49.96

 

The cytoskeleton is important for determination of cell shape, organelle transport and cell movement. Compared to the vast body of research devoted to the role of cytoskeletal components in determining neuronal shape, the study of melanocytic dendricity received very little attention (for review see Naeyaert, 1993). Recent data suggest that actin microfilaments are implicated in dendrite outgrowth, but not in maintenance, and conversely, that microtubules are involved in dendrite maintenance, but not in formation (Lacour et al., 1992). Even less is known about another crucial characteristic of melanocyte differentiation, the movement of melanosomes.

Motor proteins are closely associated with cytoskeletal components and uptil now have received little attention in the study of melanocytic dendricity and melanosome transport.

Myosins are actin-dependent motor proteins and for readers who have not kept up with literature, it will be surprising to see how much the knowledge on myosins has extended during the last years. Classically, myosins have been divided into two distinct classes: myosin II and myosin I. The myosins II include the conventional two-headed, filament-forming dimeric myosins with a coiled-coil tail, found in muscle and virtually all non-muscle cells. The term 'myosin I' was originally used to identify an unusual monomeric, single-headed myosin that was found in an amoebe and typically lacks the coiled-coil tail. Later, it appeared to be present in almost all vertebrate tissues. Given the structural difference with myosin II, myosin I was referred to as an unconventional myosin. A large number of recent studies make it clear that myosins I are not the only unconventional myosins at all. Indeed, there is a growing family of unconventional myosins that differ in structure, distribution and function. Therefore, two groups (Cheney et al., 1993; Goodson et al., 1993) suggested a more accurate classification based on phylogenetic comparisons with at least eight classes of (conventional and unconventional) myosins. Roman numerals indicate the order of discovery after myosin I and II.

Class V myosins have characteristics of both myosins I and II and are represented by the products of the mouse dilute gene (Mercer et al., 1991), the chicken p190 gene (Espreafico et al., 1992), the human "myoxin" gene (Engle et al., 1994) and the myo2/myo4 genes in yeast (Johnston et al., 1991).

As is often the case in melanocyte biology, murine mutations have provided further information on the potential function of these myosins. Mice that have the original dilute homozygous recessive mutation (dv) at the dilute gene located on chromosome 9 have short, stubby dendrites while possessing normal amounts of pigment granules that remain packaged in the perinuclear area. This abnormality disturbs the transfer of pigment from melanocytes to the surrounding keratinocytes, so that, in vivo, these mice exhibit a washed-out or diluted coat colour. These findings suggest that this class of myosin may perhaps associate with cytoplasmic vesicles, the melanosomes, serving to transport them to outer regions of the melanocyte.

Furthermore, it suggests that the dilute myosin is required for the elaboration and/or maintenance of the cellular processes of melanocytes.

In addition to dv, several spontaneous and mutagen-induced dilute alleles have been identified.

Whereas dv only affects coat colour, most of these alleles (dilutelethal - diluteopisthotonus) result in severe neurological defects and/or death in the homozygous status, indicating that the dilute gene product has an essential function.

Additionally, mutations in the yeast myo2-gene result in large, unbudded cells that accumulate vesicles within their cytoplasm (Johnston et al., 1991). This has been interpreted as further evidence for a role for this member of the myosin V family in intracellular vesicle transport.

Very often, murine genetics have opened the way for unpuzzling the pathogenesis of human genodermatoses concerning cutaneous pigmentation (Ortonne, 1993). The human counterpart of the dilute mutation might be found in the Griscelli Pruniéras syndrome, a very rare autosomal recessive disease, of which the genetic locus has not yet been identified. This syndrome is characterized by partial albinism, silver-blond hair discoloration, primary immuno-deficiency and, frequently, neurological deficits. Ultrastructural analysis of skin sections shows a characteristic appearance of melanocytes with short, stubby dendrites. The melanocytes are packaged with mature melanosomes, indicating a transfer block towards the surrounding keratinocytes. These structural alterations are very reminiscent of those seen in melanocytes of dilute mice. The myoxin locus on chromosome 15 is a good candidate for mutation analysis in this disease.

The available data clearly suggest an important role of myosins in the elaboration, maintenance or function of melanocytic dendrites and the participation of these motor proteins in the intracellular transport of melanosomes. However, it is likely that unconventional myosins participate in very complex cellular structures that require a multitude of cytoskeletal proteins and that are driven by multiple mechanisms. Cooperation between the actin-based motor myosin and microtubuli-based motors such as kinesin and dynein also remains to be elucidated in melanocytes.

References

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- Engle L.J., Kennett R.H. Cloning, analysis, and chromosomal localization of myosin (MYH12), the human homologue to the mouse dilute gene. Genomics 19:407-416, 1994.
- Espreafico E.M., Cheney R.E., Matteoli M., Nascimento A.A.C., De Camilli P.V., Larson R.E., Mooseker M.S. Primary structure and cellular localization of chicken brain myosin-V (p 190), an unconventional myosin with calmodulin light chains. J.Cell Biol. 119:1541-1557, 1992.
- Goodson H.V., Spudigh J.A. Molecular evolution of the myosin family: relationships derived from comparisons of amino acid sequences. Proc. Natl. Acad. Sci. USA 90 : 659-663, 1993.
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- Mercer J.A., Seperack P.K., Strobel M.C., Copeland N.G., Jenkins N.A. Novel myosin heavy chain encoded by murine dilute coat colour locus. Nature 349:709-7l3, 1991.
- Naeyaert J.M., Lacour J.M. Biologie cellulaire du mélanocyte humain normal. Médecine Sciences 9:431-440, 1993.
- Ortonne J.P. Les genodermatoses pigmentaires: une histoire de souris et d'hommes (Editorial). Médecine Sciences 9:373-375, 1993.