Epistatic and independent functions of caspase-3 and Bcl-X(L) in developmental programmed cell death.
The number of neurons in the mammalian brain is determined by a balance between cell proliferation and programmed cell death. Recent studies indicated that Bcl-X(L) prevents, whereas Caspase-3 mediates, cell death in the developing nervous system, but whether Bcl-X(L) directly blocks the apoptotic function of Caspase-3 in vivo is not known. To examine this question, we generated bcl-x/caspase-3 double mutants and found that caspase-3 deficiency abrogated the increased apoptosis of postmitotic neurons but not the increased hematopoietic cell death and embryonic lethality caused by the bcl-x mutation. In contrast, caspase-3, but not bcl-x, deficiency changed the normal incidence of neuronal progenitor cell apoptosis, consistent with the lack of expression of Bcl-X(L) in the proliferative population of the embryonic cortex. Thus, although Caspase-3 is epistatically downstream to Bcl-X(L) in postmitotic neurons, it independently regulates apoptosis of neuronal founder cells. Taken together, these results establish a role of programmed cell death in regulating the size of progenitor population in the central nervous system, a function that is distinct from the classic role of cell death in matching postmitotic neuronal population with postsynaptic targets.
Roth
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KA
Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA. kroth@pathology.wustl.edu
Kuan
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C
Haydar
T F
TF
D'Sa-Eipper
C
C
Shindler
K S
KS
Zheng
T S
TS
Kuida
K
K
Flavell
R A
RA
Rakic
P
P
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001921:Brain / Q000196:embryology; D053148:Caspase 3; D020169:Caspases / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D005838:Genotype; D006651:Histocytochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009420:Nervous System / Q000196:embryology*; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases