The death and survival of neuronal cells are regulated by various signaling pathways during development of the brain and in neuronal diseases. Previously, we demonstrated that the neuronal adhesion molecule brain immunoglobulin-like molecule with tyrosine-based activation motifs/SHP substrate 1 (BIT/SHPS-1) is involved in brain-derived neurotrophic factor (BDNF)-promoted neuronal cell survival. Here, we report the apoptosis-inducing effect of CD47/integrin-associated protein (IAP), the heterophilic binding partner of BIT/SHPS-1, on neuronal cells. We generated a recombinant adenovirus vector expressing a neuronal form of CD47/IAP, and found that the expression of CD47/IAP by infection with CD47/IAP adenovirus induced the death of cultured cerebral cortical neurons. The numbers of TdT-mediated biotin-dUTP nick-end labelling (TUNEL)-positive neurons and of cells displaying apoptotic nuclei increased by expression of CD47/IAP. Neuronal cell death was prevented by the addition of the broad-spectrum caspase inhibitor Z-VAD-fmk. Furthermore, we observed that co-expression of CD47/IAP with BIT/SHPS-1 enhanced neuronal cell death, and that BDNF prevented it. These results suggest that CD47/IAP is involved in a novel pathway which regulates caspase-dependent apoptosis of cultured cerebral cortical neurons. CD47/IAP-induced death of cultured cortical neurons may be regulated by the interaction of CD47/IAP with BIT/SHPS-1 and by BDNF. CD47/IAP (integrin-associated protein), originally identified through co-purification with the integrin a v b 3 from human placenta, is a 50-kDa protein possessing a V-type immunoglobulin domain in its extracellular domain, a five membranespanning domain and a short cytoplasmic tail (Brown et al. 1990;Rosales et al. 1992;Lindberg et al. 1993;Lindberg et al. 1994). CD47/IAP shows a very broad cell and tissue distribution along with neuronal cells (Mawby et al. 1994). There are four alternative splicing variants of CD47/IAP that differ from each other at their cytoplasmic tails (Reinhold et al. 1995). The neuronal form of CD47/IAP, Form 4, has the longest cytoplasmic tail (Reinhold et al. 1995).Studies in non-neuronal cells revealed that CD47/IAP regulates some adhesion-dependent cell functions, e.g. migration of neutrophils (Cooper et al. 1995;Parkos et al. 1996) and platelet spreading and aggregation (Chung et al. 1997;Chung et al. 1999). CD47/IAP-deficient animals have a defect in host defense that results from lack of phagocyte activation at the site of infection (Lindberg et al. 1996). In neutrophils and endothelial cells, several reports have shown that CD47/IAP is involved in the apoptosis inducing signaling (Mateo et al. 1999;Pettersen et al. 1999;Freyberg et al. 2000;Pettersen 2000;Freyberg et al. 2001 Abbreviations used: BDNF, brain-derived neurotrophic factor; BIT, brain immunoglobulin-like molecule with tyrosine-based activation motifs; IAP, integrin-associated protein; MAP2, microtubule-associated protein 2; MOI, multiplicity of infection; PBS, phosphate-buffered saline; SH...

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