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Volume 16, Number 19, Issue of October 1, 1996 pp. 6134-6145
Copyright ©1996 Society for NeuroscienceNeuron Death in the Substantia Nigra of Weaver Mouse Occurs Late in Development and Is Not Apoptotic
Received May 30, 1996; revised July 11, 1996; accepted July 15, 1996.
Tinmarlar F. Oo1, Richard Blazeski2, Susan M. W. Harrison3, Claire Henchcliffe1, Carol A. Mason2, Suzanne K. Roffler-Tarlov3, and Robert E. Burke1 1 Department of Neurology, and 2 Departments of Pathology, and Anatomy and Cell Biology, Center for Neurobiology and Behavior, College of Physicians and Surgeons, Columbia University, New York, New York 10032, and 3 Departments of Neuroscience, and Anatomy and Cell Biology, Tufts University, Boston, Massachusetts 02111
Weaver is a spontaneous mutation in mice characterized by the postnatal loss of external granule cells in the cerebellum and dopaminergic neurons of the midbrain, especially in the substantia nigra. We have shown previously that natural cell death with the morphology of apoptosis occurs in the substantia nigra of normal rodents during postnatal development. We therefore sought to determine whether the loss of dopaminergic neurons in homozygous weaver mice occurs during the period of natural cell death in the substantia nigra and whether it has the morphology of apoptosis. We have found, using a silver stain technique, that although apoptotic cell death does occur early postnatally in homozygous weaver substantia nigra, it also does so with equal magnitude in wild-type and heterozygous weaver littermates. Unique to homozygous weavers is the occurrence of degenerating neurons in the nigra that are not apoptotic. These degenerating neurons are observed at postnatal day 7, and they are most abundant on postnatal days 24-25. The nonapoptotic nature of this cell death is confirmed by negative in situ end labeling of nuclear DNA fragmentation and by ultrastructural analysis. Ultrastructural studies reveal irregular chromatin aggregates in the nucleus, as well as marked cytoplasmic changes, including the formation of vacuoles and distinctive stacks of dilated cisternae of endoplasmic reticulum. We interpret these changes as indicative of either a variant morphology of programmed cell death or a pathological degenerative process mediated by an as yet unknown mechanism related to the recently described mutation in the GIRK2 potassium channel.
Key words: weaver; apoptosis; programmed cell death; substantia nigra; potassium channel; development; ultrastructure
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