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J Comp Neurol. 2000 Jul 17;423(1):1-12.

Decreased apoptosis in proliferative and postmitotic regions of the Caspase 3-deficient embryonic central nervous system.

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Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, California 92093-0636, USA.


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.

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