Macrophage stimulating protein is a novel neurotrophic factor

Macrophage stimulating protein (MSP), also known as hepatocyte growth facto r-like, is a soluble cytokine that belongs to the fan-Lily of the plasminog en-related growth factors (PRGFs). PRGFs are alpha/beta heterodimers that b ind to transmembrane tyrosine kinase receptors. MSP was originally isolated as a chemotactic factor for peritoneal macrophages. Through binding to its receptor, encoded by the RON gene, it stimulates dissociation of epithelia and works as an inflammatory mediator by repressing the production of nitr ic oxide (NO). Here, we identify a novel role for MSP in the central nervou s system. As a paradigm to analyze this function we chose the hypoglossal s ystem of adult mice. We demonstrate in vivo that either administration of e xogenous MSP or transplantation of MSP-producing cells at the proximal stum p of the resected nerve is sufficient to prevent motoneuron atrophy upon ax otomy. We also show that the MSP gene is expressed in the tongue, the targe t of the hypoglossal nerve, and that MSP induces biosynthesis of Ron recept or in the motoneuron somata. Finally, we show that MSP suppresses NO produc tion in the injured hypoglossal nuclei. Together, these data suggest that M SP is a novel neurotrophic factor for cranial motoneurons and, by regulatin g the production of NO, may have a role in brain plasticity and regeneratio n.