Attractin, initially discovered as a human secreted glycoprotein circulating at high concentrations in the periphery and enabling T cell-monocyte clustering (1), also exists as a transmembrane form produced by alternative splicing of the ATRN gene, while the mouse only produces the transmembrane form (2, 3). On activated T cells, attractin moves in electron-dense proteoglycan-rich vesicles to the plasma membrane leading to transient extracellular expression (1, 4). Mutations at the Atrn locus in the mouse result in the mahogany phenotype where, despite normal levels of the agouti protein that acts as an antagonist of α-melanocyte stimulating hormone (α-MSH), the agouti protein does not appear to be appropriately presented to the Melanocortin-1 receptor (Mc1R) and black/brown eumelanin synthesis persists rather than that of the lighter yellowish phaeomelanin (2). Attractin’s role in agouti presentation remains to be fully elucidated. One possibility is that the membrane-anchored ectodomain may help present agouti protein by binding the positive N-terminal leaving the C-terminal free to interact with the Mc1R (5).
Attractin’s functional range has widened following reports that mahogany (Atrnmg−3J/mg−3J) mice present a juvenile-onset Central Nervous System (CNS)-confined neurodegeneration characterized by hypomyelination, axonal swelling, spongiform vacuolation and microtremors (5). This neural phenotype is found not only in other mouse mutant Atrn alleles (6, 7) but also in the zitter and myelin vacuolation rats (8, 9), and the black tremor hamster (10), all now confirmed as Atrn mutants. The pigmentation phenotype and neuropathology are corrected in animals transgenic for membrane attractin (5, 8). Embryonic development appears normal in Atrn-mutant mice; the neurodegeneration is manifest during juvenile maturation and may be related to a defect in maintaining the integrity of the plasma membrane with potentially severe consequences for oligodendrocyte-directed myelination (4, 11). Attractin’s common biochemical role in immune cell interactions, regulation of pigmentation and neural pathology remains undefined. A function in vesicular transport of cargo, both proteoglycan and new lipid-raft rich membrane, to the plasma membrane is implicated.