c-neu oncoprotein in developing rostral cerebral cortex: relationship to epidermal growth factor receptor

The c-neu oncoprotein, p185c-neu, is a transmembrane tyrosine kinase that shares structural similarities with the receptor for epidermal growth factor (EGFr). We used immunoblots, immunoprecipitation, and immunohistochemistry 1) to test the hypothesis that p185c-neu and EGFr are coordinately expressed in central nervous system tissue and 2) to assess the spatiotemporal expression of both the c-neu oncoprotein and EGFr in the rostral cerebral cortex. In nondenaturing gels, anti-c-neu antibody identified high molecular weight proteins (about 300-400 kDa) that were reduced by EDTA to a molecular weight of 180-200 kDa. Sodium dodecylsulfate polyacrylamide gel electrophoresis broke down this protein into an array of smaller peptides, which were expressed prenatally, transiently during the first three postnatal weeks, or in the adult. Perinatally, c-neu immunoreactivity was evident in subplate neurons, ascending processes of neurons in the cortical plate, and ventricular zone cells. During the second postnatal week, cells throughout cortex expressed somatodendritic immunostaining, but, in the adult, c-neu immunoreactivity was expressed only by pyramidal neurons in layer V and by glia in the white matter and ependyma. EGFr-positive proteins behaved in the nondenaturing gels as did c-neu-positive oncoproteins, suggesting that both proteins naturally formed dimers. This contention was supported by the EGFr-or c-neu immunolabeling of tissue that was previously immunoprecipitated with anti-c-neu or anti-EGFr, respectively. The pattern of EGFr immunolabeling in the developing and mature cortex was virtually identical to that described for c-neu immunoreactivity. Cortical neurons express the c-neu oncoprotein and EGFr, probably as heterodimers. The specific immunolabeling of layer V neurons in the adult cortex with anti-c-neu and anti-EGFr suggests that the p185c-neu ligand and EGF regulate the activity of corticofugal systems. The expression of different c-neu- and EGFr-positive peptides is developmentally defined and may be related to specific ontogenetic events.