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 the hind limbs, and death at 3-4 weeks after birth. Previous studies showed that rats homozygous for the mutation have a dramatically reduced brain size caused by a burst of apoptosis that begins after embryonic day 16 (E16) and 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 glia are both affected by the mutation. Immunohistochemical analysis with TAG-1, a marker for migratory neurons, revealed reduced staining in Fh neocortex and cerebellum, indicating that the mutation affects 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 progenitor cells were multinucleated with the nuclei organized as rosettes. Such multinucleated cells were also found in intact sections of the neocortex and the cerebellum where their presence was restricted to proliferative zones. Within the neocortex, the abundance of multinucleated progenitors is highest at E18 and decreases thereafter, thus correlating with the profile of cell death. This, along with the dramatically higher frequency of apoptosis 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.
Mitchell
B D
BD
Department of Molecular and Cell Biology, University of Texas at Dallas, 2601 North Floyd Road, Richardson, TX 75083, USA.
Gibbons
B
B
Allen
L R
LR
Stella
J
J
D'Mello
S R
SR
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D015816:Cell Adhesion Molecules, Neuronal; D002455:Cell Division / Q000235:genetics; D002531:Cerebellum / Q000002:abnormalities* / Q000473:pathology; D058969:Contactin 2; D004247:DNA / Q000096:biosynthesis; D015726:Giant Cells / Q000737:chemistry / Q000166:cytology; D020287:In Situ Nick-End Labeling; D007381:Intermediate Filament Proteins / Q000032:analysis; D008562:Membrane Glycoproteins / Q000032:analysis; D019579:Neocortex / Q000002:abnormalities* / Q000473:pathology; D009419:Nerve Tissue Proteins; D064231:Nestin; D009457:Neuroglia / Q000166:cytology; D009474:Neurons / Q000737:chemistry / Q000166:cytology*; D051381:Rats; D011922:Rats, Mutant Strains; D012886:Skull / Q000002:abnormalities; D013234:Stem Cells / Q000737:chemistry / Q000166:cytology*
D015816:Cell Adhesion Molecules, Neuronal; C548676:Cntn2 protein, rat; D058969:Contactin 2; D007381:Intermediate Filament Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C577486:Nes protein, rat; D064231:Nestin; D004247:DNA