Schwann cell lineage-specific neu (erbB-2) gene expression in the developing rat nervous system

Initiation of oncogenesis in the immature peripheral nervous system (PNS) of rats by the DNA-reactive carcinogen N-ethyl-N-nitrosourea (EtNU) involves a specific T:A-->A:T transversion mutation at nucleotide 2012 of the neu (erbB-2) receptor tyrosine kinase gene in cells of the Schwann cell lineage. Although this mutation is invariably detected in the resulting malignant schwannomas, it is not found in EtNU-induced tumors of the central nervous system (CNS). We have evaluated expression of the neu gene in the PNS and CNS as a function of developmental stage. Cellular levels of neu mRNA and gp185neu were analyzed in the trigeminal and sciatic nerve and in brain, using a quantitative reverse transcription-polymerase chain reaction, in situ hybridization, immunocytochemistry, and fluorescence-activated cell sorting. In the PNS, expression of the neu gene is restricted to cells of the Schwann cell lineage and markedly exceeds expression in the CNS from prenatal day 20 onward. In trigeminal Schwann cells, neu mRNA is most abundant (2.8 x 10(7) copies/micrograms of RNA) on postnatal day 1, coincident with both the end of maximum mitotic activity and the "developmental window" of highest sensitivity to malignant transformation by EtNU. The subsequent decrease of neu gene expression is accompanied by decreasing proliferative activity and the onset of myelination. The level of neu gene expression may thus be critical to proliferation versus differentiation decisions in the Schwann cell lineage. EtNU-induced mutation of the neu gene in proliferative Schwann cell precursors expressing gp185neu may abrogate their responsiveness to extracellular and/or intrinsic controls, resulting in sustained proliferative activity and malignant conversion.