Myelin proteolipid protein (Plp) intron 1 DNA is required to temporally regulate Plp gene expression in the brain

Abstract

The myelin proteolipid protein (Plp) gene encodes the most abundant protein found in mature CNS myelin. Expression of the gene is regulated spatiotemporally, with maximal expression occurring in oligodendrocytes during the myelination period of CNS development. Plp gene expression is tightly controlled. Misregulation of the gene in humans can result in the dysmyelinating disorder Pelizaeus–Merzbacher disease, and in transgenic mice carrying a null mutation or extra copies of the gene can result in a variety of conditions, from late onset demyelination and axonopathy, to severe early onset dysmyelination. Previous transfection studies suggest that the first intron contains elements that are vital for directing Plp gene activity, spatiotemporally. Here we verify, in vivo, the importance of these regulatory elements by the use of a Plp‐lacZ transgene [PLP(–)Z], which does not contain any Plp intron 1 sequence. The developmental profile of PLP(–)Z expression in transgenic mice is flat throughout the active myelination period of brain development, whereas mice which harbor a related transgene [PLP(+)Z] that contains the first intron, demonstrate the expected surge in oligodendroglial expression during this period. Although lacZ expression was extremely low in the brains of PLP(–)Z mice (and could not be detected in oligodendrocytes by X‐gal staining), expression in the testes was far more abundant and restricted to Leydig cells. Similar levels of lacZ expression were detected in the testes of PLP(+)Z mice. Thus, intron 1 DNA contains regulatory sequences critical for Plp gene expression in oligodendrocytes, but may not be required for expression in other cell types.