Programmed cell death of developing mammalian neurons after genetic deletion of caspases.
An analysis of programmed cell death of several populations of developing postmitotic neurons after genetic deletion of two key members of the caspase family of pro-apoptotic proteases, caspase-3 and caspase-9, indicates that normal neuronal loss occurs. Although the amount of cell death is not altered, the death process may be delayed, and the cells appear to use a nonapoptotic pathway of degeneration. The neuronal populations examined include spinal interneurons and motor, sensory, and autonomic neurons. When examined at both the light and electron microscopic levels, the caspase-deficient neurons exhibit a nonapoptotic morphology in which nuclear changes such as chromatin condensation are absent or reduced; in addition, this morphology is characterized by extensive cytoplasmic vacuolization that is rarely observed in degenerating control neurons. There is also reduced terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling in dying caspase-deficient neurons. Despite the altered morphology and apparent temporal delay in cell death, the number of neurons that are ultimately lost is indistinguishable from that seen in control animals. In contrast to the striking perturbations in the morphology of the forebrain of caspase-deficient embryos, the spinal cord and brainstem appear normal. These results are consistent with the growing idea that the involvement of specific caspases and the occurrence of caspase-independent programmed cell death may be dependent on brain region, cell type, age, and species or may be the result of specific perturbations or pathology.
Oppenheim
R W
RW
Department of Neurobiology and Anatomy and the Neuroscience Program, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. roppenhm@wfubmc.edu
Flavell
R A
RA
Vinsant
S
S
Prevette
D
D
Kuan
C Y
CY
Rakic
P
P
D000818:Animals; D017209:Apoptosis; D001933:Brain Stem / Q000166:cytology; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D002452:Cell Count; D002470:Cell Survival / Q000235:genetics; D005724:Ganglia / Q000166:cytology; D006720:Homozygote; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009436:Neural Tube Defects / Q000235:genetics / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D016548:Prosencephalon / Q000002:abnormalities / Q000473:pathology; D013116:Spinal Cord / Q000473:pathology
C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases