The evolution of lipophilin genes from invertebrates to tetrapods: DM-20 cannot replace proteolipid protein in CNS myelin

The proteolipid protein (PLP) gene encodes two myelin-specific protein isof orms, DM-20 and PLP, which are members of the highly conserved lipophilin f amily of transmembrane proteins. While the functions of this family are poo rly understood, the fact that null mutations of the PLP gene cause leukodys trophy in man is testament to the importance of DM-20 and PLP in normal CNS function. PLP differs from DM-20 by the presence of a 35 amino acid domain exposed to the cytoplasm, which is not encoded by other lipophilin genes a nd appears to have arisen in amphibians similar to 300 million years before present. However, the lipophilin gene family can be traced back at least 5 50 million years and is represented in Drosophila and silkworms. Thus, from an evolutionary perspective PLP can reasonably be anticipated to perform f unctions in CNS myelin that cannot be accomplished by other lipophilins. He rein we use a novel knock-in strategy to generate mice expressing wild-type levels of a Plp gene that has been modified to encode only DM-20. Although DM-20 is incorporated into functional compact myelin sheaths in young anim als, our data show that the 35 amino acid PLP-specific peptide is required to engender the normal myelin period and to confer long-term stability on t his multilamellar membrane.