The proto-oncogene RON is involved in development of epithelial, bone and neuro-endocrine tissues

We previously showed that the proto-oncogene RON encodes the tyrosine kinase receptor for Macrophage Stimulating Protein (MSP), originally isolated as a chemotactic factor for peritoneal macrophages. To elucidate the biological role of MSP we studied the expression of the Ron receptor in vivo, and the response to the factor in vitro. RON specific transcripts were detectable in mouse liver from early embryonal life (day 12.5 p.c.) through adult life. Adrenal gland, spinal ganglia, skin, lung and - unexpectedly - ossification centers of developing mandible, clavicle and ribs were also positive at later stages (day 13.5-16.5 p.c.). From day 17.5 RON was expressed in the gut epithelium and in a specific area of the central nervous system, corresponding to the nucleus of the hypoglossus. In adult mouse tissues RON transcripts were observed in brain, adrenal glands, gastro-intestinal tract, testis and kidney. Epithelial, osteoclast-like and neuroendocrine cells express the Ron receptor and respond to MSP in vitro. In the neuroendocrine PC12 cell line, while NGF induced growth arrest and morphological differentiation, MSP behaved as a strong mitogen. These findings show that the Ron receptor and its ligand are involved in the development of epithelial tissues, bones, and neuroendocrine derivatives driving cells towards the proliferation program.