Fas/Apo [apoptosis]-1 and associated proteins in the differentiating cerebral cortex: Induction of caspase-dependent cell death and activation of NF-kappa B

The developing cerebral cortex undergoes a period of substantial cell death . The present studies examine the role of the suicide receptor Fas/Apo[apop tosis]-1 in cerebral cortical development. Fas mRNA and protein are transie ntly expressed in subsets of cells within the developing rat cerebral corte x during the peak period of apoptosis. Fas-immunoreactive cells were locali zed in close proximity to Fas ligand (FasL)-expressing cells. The Pas-assoc iated signaling protein receptor interacting protein (RIP) was expressed by some Fas-expressing cells, whereas Fas-associated death domain (FADD) was undetectable in the early postnatal cerebral cortex. FLICE-inhibitory prote in (FLIP), an inhibitor of Fas activation, was also expressed in the postna tal cerebral cortex. Fas expression was more ubiquitous in embryonic cortic al neuroblasts in dissociated culture compared to in situ within the develo ping brain, suggesting that the environmental milieu partly suppresses Fas expression at this developmental stage. Furthermore, FADD, RIP, and FLIP we re also expressed by subsets of dissociated cortical neuroblasts in culture . Fas activation by ligand (FasL) or anti-fas antibody induced caspase-depe ndent cell death in primary embryonic cortical neuroblast cultures. The act ivation of Fas was also accompanied by a rapid downregulation of FEIS recep tor expression, non-cell cycle-related incorporation of nucleic acids and n uclear translocation of the RelA/p65 subunit of the transcription factor NF -kappa B. Together, these data suggest that adult cortical cell number may be established, in part, by an active process of receptor-mediated cell sui cide, initiated in situ by killer (FasL-expressing) cells and that Fas may have functions in addition to suicide in the developing brain.