Programmed cell death without DNA fragmentation in the jimpy mouse: secreted factors can enhance survival

Jimpy is one of many related mutations affecting the myelin proteolipid pro tein gene that causes severe hypomyelination in the central nervous system (CNS). Underlying the hypomyelination is a failure of oligodendrocytes (Ols ) to differentiate, and the premature death of large numbers of OLs during the developmental period, previous light and electron microscopic evidence suggested that jimpy OLs die in a manner consistent with programmed cell de ath. We have used TUNEL staining as a biochemical marker for apoptosis in c onjunction with immunostaining for OL and myelin markers. At 13 - 14 days p ostnatal, a time when the number of dying OLs in jimpy CNS is increased mor e than five times normal, there are only modest increases (70% in spinal co rd; 20% in cerebral cortex) in TUNEL labeled cells in mutant CNS tissues. T he results in vitro ave similar, and only a small per cent of TUNEL labeled cells have the antigenic phenotype of OLs. The discrepancy between numbers of dying and TUNEL labeled cells suggests either that most jimpy OLs do no t undergo programmed cell death or that the biochemical pathways leading to their death do not involve DNA fragmentation which is detected by the TUNE L method. We also present evidence that jimpy OLs show increased survival a nd enhanced differentiation when they are grown in vitro in medium conditio ned by cells lines which express products of the proteolipid protein gene. Cell lines expressing proteolipid protein and the alternatively spliced DM2 0 protein have differential effects on cell numbers and production of myeli n-like membranes.