title: Decreased apoptosis in proliferative and postmitotic regions of the Caspase 3-deficient embryonic central nervous system.
abstract: Caspase 3 (CPP32/Yama/apopain), a mammalian homolog of the Caenorhabditis elegans pro-cell death gene ced-3, is required for normal programmed cell death (PCD) in the nematode. Its prior deletion by homologous recombination in mice resulted in embryonic/early postnatal lethality associated with dramatic central nervous system (CNS) hyperplasia, yet a reported subtle decrease in cell death (Kuida et al. [1996] Nature 384:368-372). By comparison, the magnitude and distribution of dying cells identified using a DNA end-labeling technique, in situ end-labeling plus (ISEL+) (Blaschke et al. [1996] Development 122:1165-1174; Blaschke et al. [1998] J. Comp. Neurol. 396:39-50), supported an alternative explanation where the loss of caspase 3 function produces a more pervasive block in cell death, particularly among neuroblasts. To determine the relationship between loss of caspase 3 and dying cells identified by ISEL+, we analyzed caspase 3 +/+, +/-, and -/- embryos for normal caspase 3 expression and ISEL+ labeling. Both caspase 3 mRNA and active caspase 3 protein are present throughout the +/+ embryonic CNS, and both are absent from -/- embryonic cortices. Quantitation of dying cells identified by ISEL+ reveals a 30% reduction of labeled cells throughout the caspase 3 -/- embryonic cortices relative to +/+ littermates. Associated with this decrease is marked expansion of the total population of actively proliferating neuroblasts identified by 5-bromo-2;-deoxyuridine incorporation that nevertheless appears to maintain histological features of normal neurogenesis rather than dysregulated, neoplastic growth. These data indicate that caspase 3 deficiency results in a pervasive, albeit partial, decrease in embryonic neuroblast apoptosis that can account for the observed phenotypic hyperplasia in -/- embryos, and support the additional operation of caspase 3-independent PCD mechanisms during embryonic CNS development.
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, California 92093-0636, USA.
authors.forename: M
authors.initials: M
authors.lastname: Pompeiano
authors.forename: A J
authors.initials: AJ
authors.lastname: Blaschke
authors.forename: R A
authors.initials: RA
authors.lastname: Flavell
authors.forename: A
authors.initials: A
authors.lastname: Srinivasan
authors.forename: J
authors.initials: J
authors.lastname: Chun
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D053148:Caspase 3; D020169:Caspases / Q000172:deficiency* / Q000235:genetics*; D002455:Cell Division / Q000235:genetics*; D002490:Central Nervous System / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008938:Mitosis / Q000502:physiology*; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases