Aberrant apoptosis in the neurological mutant Flathead is associated with defective cytokinesis of neural progenitor cells

Flathead is a rat neurological mutant which is phenotypically characterized by a flattened cranium, resting tremor, ataxia, progressive paralysis of t he hind limbs, and death at 3-4 weeks after birth. Previous studies showed that rats homozygous for the mutation have a dramatically reduced brain siz e caused by a burst of apoptosis that begins after embryonic day 16 (E16) a nd which peaks at about E18. Late-developing structures such as the dentate gyrus, internal granule layer of the cerebellum, and superficial layers of the neocortex are severely depleted of cells. In the present study we have found that neurons and gIia are both affected by the mutation. Immunohisto chemical analysis with TAG-1, a marker for migratory neurons, revealed redu ced staining in Fh neocortex and cerebellum, indicating that the mutation a ffects neuronal migration or a developmental event prior to it. Analysis of acutely dissociated neocortical cultures showed an accumulation of nestin- positive progenitor cells. Moreover, a substantial proportion of these prog enitor cells were multinucleated with the nuclei organized as rosettes. Suc h multinucleated cells were also found in intact sections of the neocortex. and the cerebellum where their presence was restricted to proliferative zo nes. Within the neocortex, the abundance of multinucleated progenitors is h ighest at E18 and decreases thereafter, thus correlating with the profile o f cell death. This, along with the dramatically higher frequency of apoptos is among multinucleated cells, suggests that the aberrant cell death in Fh is due to defective cytokinesis that occurs in progenitor cells during late stages of brain development. (C) 2001 Elsevier Science B.V. All rights res erved.