Cell death in the midbrain of the murine mutation weaver

Abstract

The midbrain of the adult homozygous weaver (wv/wv) mouse is notable for a reduction in the numbers of dopamine-containing cells in the substantia nigra (A9) and the retrorubral nucleus (A8). We have determined that the reduction in tyrosine hydroxylase (TH)-positive neurons in the ventral midbrain of the weaver is attributable to the loss of neurons after postnatal day 7 (P7). Because the number and spatial distribution of TH-positive mesencephalic neurons in wv/wv, heterozygous weavers (+/wv), and wild-type mice are not significantly different on P7, we conclude that the early developmental steps of proliferation and migration have taken place normally in the mutant. Although numbers and distribution of cells are normal in the wv/wv on P7, the appearance of the TH-stained ventral midbrain is abnormal because of the paucity of TH-stained dendritic processes. The ventrally extending TH-positive dendrites are largely absent in the young wv/wv. The wv/wv also can be distinguished from both homozygous normal (+/+) and wv/wv littermates on P7 based on the appearance of dendrites that are more numerous than in the wv/wv but thin, disorganized, and sparse compared with +/+. Most cell death seems to take place in wv/wv before P21. However, at least one subset of dopamine-containing neurons disappears later. The zone of densely packed TH-positive neurons in the substantia nigra that is likely to be the origin of innervation to striosomes in the caudoputamen disappears between P21 and adulthood. Despite the early pathology evident in the mesencephalic dopamine-producing neurons of the +/wv, no evidence for cell death was observed there even in the oldest +/wv weavers studied.