Disruption of the compacted myelin sheath of axons of the central nervous system in proteolipid protein-deficient mice.

The isoproteins proteolipid protein (PLP) and DM20, the two major integral membrane proteins of central nervous system (CNS) myelin, are encoded by a single gene on the X chromosome and show a different developmental expression pattern. To investigate their functions in myelin structure and myelination, we produced transgenic mice carrying a targeted alteration of the X chromosome-linked Plp gene containing a deletion within exon III, mimicking DM20, and a neo cassette in reverse orientation within intron III. Here we show that the antisense integration of the neo cassette disrupts the expression of the Plp gene. The ultrastructure of the multilayer myelin sheath of all axons in the CNS of hemizygous male or homozygous female PLP/DM20-deficient mice is highly disordered. The apposition of the extracytoplasmic surfaces and thereby the intraperiod dense line is lacking. The disrupted assembly of the myelin sheath leads to a profound reduction of conductance velocities of CNS axons, impairments in neuromotor coordination, and behavioral changes.