Macrophage stimulating protein is a novel neurotrophic factor.
Macrophage stimulating protein (MSP), also known as hepatocyte growth factor-like, is a soluble cytokine that belongs to the family of the plasminogen-related growth factors (PRGFs). PRGFs are alpha/beta heterodimers that bind 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 nitric oxide (NO). Here, we identify a novel role for MSP in the central nervous system. As a paradigm to analyze this function we chose the hypoglossal system of adult mice. We demonstrate in vivo that either administration of exogenous MSP or transplantation of MSP-producing cells at the proximal stump of the resected nerve is sufficient to prevent motoneuron atrophy upon axotomy. We also show that the MSP gene is expressed in the tongue, the target of the hypoglossal nerve, and that MSP induces biosynthesis of Ron receptor in the motoneuron somata. Finally, we show that MSP suppresses NO production in the injured hypoglossal nuclei. Together, these data suggest that MSP is a novel neurotrophic factor for cranial motoneurons and, by regulating the production of NO, may have a role in brain plasticity and regeneration.
Stella
M C
MC
Institute for Cancer Research and Treatment, IRCC, University of Torino Medical School, 10060 Candiolo, Torino, Italy. mcstella@hal.ircc.unito.it
Vercelli
A
A
Repici
M
M
Follenzi
A
A
Comoglio
P M
PM
D000818:Animals; D019771:Axotomy; D001921:Brain / Q000378:metabolism*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D006133:Growth Substances / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017228:Hepatocyte Growth Factor; D007002:Hypoglossal Nerve / Q000166:cytology / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008959:Models, Neurological; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000235:genetics / Q000494:pharmacology*; D009474:Neurons / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000276:immunology / Q000378:metabolism; D014059:Tongue / Q000294:innervation / Q000378:metabolism
D006133:Growth Substances; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C082332:macrophage stimulating protein; D009569:Nitric Oxide; D017228:Hepatocyte Growth Factor; D019001:Nitric Oxide Synthase; D002795:Choline O-Acetyltransferase; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases