Region of caspase-3 activation and programmed cell death in the early development of the mouse forebrain

Caspase-3-deficient 129/Sv mice show hyperplasia of the brain at embryonic (E) day 10.5-12.5, but caspase-3-deficient C57L/B6 mice do not. We examined the relationship between activation of caspase-3 and programmed cell death (PCD) during forebrain development of various mouse strains (129/Sv, ICR, C57L/B6, and CBA) using terminal deoxytransferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) and immunostaining with antiserum against the caspase-3 (anti-m3D175) cleavage site. A number of anti-m3D175 positive cells and TUNEL positive cells were detected in the ventral side of the forebrain of 129/Sv and ICR mice at E8.5-9 but not in C57L/B6 and CBA mice. Ac-DEVD-MCA cleavage activity, a caspase-3-like activity, also suggests the preferential activation of caspase-3 in the ventral forebrain of ICR mice but not in C57L/B6 mice. Developmental changes of TUNEL and anti-m3D175 reactivities were essentially similar during brain morphogenesis of ICR and 129/Sv mice. The number of TUNEL/anti-m3D175 positive cells decreased in the neuroepithelium of the ventral forebrain at E9.5 before generation of the medial ganglionic eminence (MGE). TUNEL and/or anti-m3D175 reactivity was slightly detectable in the MGE at E10.5, from which neuroprogenitor cells follow a tangential migratory route to the cortex. Activation of caspase-9 was also immunohistochemically detected in the ventral forebrain at E8.5-9, suggesting that activation of caspase-3 and caspase-9 occurs in the PCD of this region. Thus, it is likely that decreased cell death in the ventral forebrain of caspase-3- and caspase-9-deficient 129/Sv mice increases the number of neuroprogenitor cells in the MGE, leading to hyperplasia of the forebrain.