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Vascular endothelial growth factor (VEGF) is an angiogenic and neurotrophic factor in both adult and neonatal animals, but its expression and role have been incompletely studied in the developing human brain. We analyzed the distribution of VEGF and its high-affinity receptor VEGFR-2 in the human forebrain and cerebellum at developmental stages from 14 weeks' gestation (WG) to the13th postnatal month. Tissue samples free of detectable neuropathologic abnormalities were assessed by immunohistochemistry and confocal microscopy using anti-human VEGF and VEGFR-2 antibodies. The VEGFR-2 was first expressed in the whole cerebral mantle and in migrating cells in the intermediate zone, whereas VEGFwas found in superficial layers of the cortical plate, in radial glia, and in the cerebellar external germinal cell layer. From 23 WG, temporospatial VEGFR-2 expression was superimposable on that ofVEGF in the cortical plate, intermediate zone, basal ganglia, limbicstructures, and external germinal cell layer. The VEGF/VEGFR-2-positive astrocytes were observed during their generation and migration from 23 WG to the first postnatal month. The VEGF-positive mature oligodendrocytes were observed in myelinating structures in the forebrain from birth and in the cerebellum from 24WG. These data suggest that VEGF and VEGFR-2 are likely involved in several aspects of human brain development.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide that belongs to the secretin/glucagon/vasoactive intestinal polypeptide superfamily. The PACAPergic system is actively expressed in the developing cerebellum of mammals. In particular, PACAP receptors are expressed by granule cell precursors suggesting a role of the peptide in neurogenesis of this cell type. Consistent with this hypothesis, several studies reported antiapoptotic effects of PACAP in the developing cerebellum. On the other hand, the sphingomyelin metabolites ceramides are recognized as important signaling molecules that play pivotal roles during neuronal development. Ceramides, which production can be induced by death factors such as FasL or TNFalpha, are involved in the control of cell survival during brain development through activation of caspase-dependent mechanisms. The present review focuses on the interactions between PACAP and ceramides in the control of granule cell survival and on the transduction mechanisms associated with the anti- and proapoptotic effects of PACAP and ceramides, respectively.

Transplantation of neuronal precursor cells (NPCs) into the central nervous system could represent a powerful therapeutical tool against neurodegenerative diseases. Unfortunately, numerous NPCs die shortly after transplantation, predominantly due to caspase-dependent apoptosis. Using a culture of cerebellar neuronal precursors, we have previously demonstrated protective effect of the neuropeptide PACAP, which suppresses ceramide-induced apoptosis by blockade of the mitochondrial apoptotic pathway. The main objective of this study was to determine whether Bax repression can promote survival of NPCs allotransplanted into a host animal. In vivo and ex vivo experiments revealed that C2-ceramide increases Bax expression, while PACAP reverses this effect. In vitro tests using cerebellar NPCs demonstrated that the Bax-specific small interfering RNA (siRNA) could reduce their death and caspase-3 cleavage within the first 24 h. BrdU-labelled NPCs were subjected to transfection procedure with or without siRNA introduction before using for in vivo transplantation. Twenty-four hours after, the allografted NPCs containing siRNA showed significantly reduced level of caspase-3 cleavage, and the volume of their implants was almost twofold higher than in the case of empty-transfected precursors. These data evidence an important role of Bax in life/death decision of grafted NPCs and suggest that RNA interference strategy may be applicable for maintaining NPCs survival within the critical first hours after their transplantation.