One of the first CPGs selected for full scale characterization was CPG15. In the adult rat, cpg15 is induced in the brain by kainate and in visual cortex by light (Nedivi et al. 1996). During development, cpg15 expression is correlated with times of afferent ingrowth, dendritic elaboration and synaptogenesis. Sequence analysis predicts a small, secreted protein that is membrane-bound by a glycosylphosphatidylinositol (GPI) linkage. To investigate the cellular function of CPG15 we used a recombinant vaccinia virus to express CPG15 in optic tectal cells of albino Xenopus tadpoles.Two days after viral infection and approximately 24 hours after the beginning of expression of foreign protein, single tectal cells were labeled with DiI. Confocal images through the entire structure of each neuron were collected at 24 hr intervals over a period of 3 days and 3-dimensional (3-D) images were reconstructed. This work was done at Cold Spring Harbor Laboratory in collaboration with Hollis Cline and her postdoc Gang-Yi Wu. We found that CPG15 promotes dendritic arbor growth in neighboring neurons through an intercellular signaling mechanism that requires its GPI link. CPG15 may represent a new class of activity-regulated, membrane-bound, growth -promoting molecules that permit equisite spatial and temporal control of neuronal structure (Nedivi et al. 1998).

     cpg15 encodes a small highly conserved protein that is attached to the extracellular membrane through a GPI anchor. Previously, it was shown that CPG15 in its membrane bound form functions as a growth-promoting molecule that enhances dendritic arbor growth in projection neurons, elaboration of presynaptic axon arbors, and synapse maturation (Nedivi et al., 1998). mRNA localization studies in cat (Corriveau, et al., 1999) and rat (Lee and Nedivi, 2002) indicate that regulation of cpg15 expression in all visual structures is biphasic, suggesting that it may play a dual role during development. cpg15 mRNA patterns are thus consistent with an early role as a survival factor during brain morphogenesis, and a later role in structural remodeling and synaptic maturation associated with developmental and adult plasticity. At the molecular level, little is known about the signals regulating apoptosis of proliferative neurons. We identified a soluble, secreted form of CPG15 expressed in embryonic brain regions undergoing rapid proliferation and apoptosis, and showed that it can protect cultured cortical neurons from apoptosis by preventing the activation of caspase 3 induced by growth factor deprivation (Putz et al., 2005). We demonstrated by intraventricular injection of a lentivirus-delivered small hairpin RNA, that endogenous CPG15 is an essential regulator of cortical progenitor survival in vivo. We further showed that CPG15 overexpression results in an enlarged, indented cortical plate and heterotopic cell masses within the ventricular zone, similar to the phenotypes of mutant mice with supernumerary forebrain progenitors. By countering apoptosis in specific subpopulations of undifferentiated neurons, CPG15 expressed during mammalian forebrain morphogenesis may help balance neuronal number affecting final brain size and shape.