title: CSF-1 deficiency in mice results in abnormal brain development.
abstract: Colony stimulating factor-1 (CSF-1) was initially identified as a growth factor for mononuclear phagocytes. This study examines the role of CSF-1 in the development of the central nervous system (CNS). CSF-1 treatment of neurons cultured from embryonic brain promoted survival and process outgrowth in a dose-dependent manner. By contrast, CSF-1 treatment of neurons cultured from the osteopetrotic (op/op) mouse, a null mutant for CSF-1, promoted significantly less process outgrowth, suggesting that there are neural abnormalities in op/op animals. Nuclease protection assays were used to determine whether CSF-1 and its receptor are expressed at times appropriate to regulate neural development. Both CSF-1 and its receptor are expressed in developing mouse brain, with a unique pattern of CSF-1 mRNA splice variant expression encoding secreted, and not membrane-bound, growth factor. To determine whether brain function is altered by null mutation of CSF-1, op/op mice were examined using electrophysiologic assays. Brainstem auditory and visual evoked potentials were both abnormal in op/op mice. Further, intracortical recordings revealed aberrant neuronal function within visual cortex and alterations in the cortical circuitry that balances excitation and inhibition. Daily CSF-1 injection of postnatal op/op mice largely rescued the abnormal neural phenotype, confirming that the absence of CSF-1 during development is responsible for the abnormalities. The effects of CSF-1 on cultured embryonic neural cells, the developmentally appropriate expression of CSF-1 and its receptor, and the neurological abnormalities in op/op mice suggest a role for CSF-1 in brain development.
authors.affiliation: Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Michaelson
authors.forename: P L
authors.initials: PL
authors.lastname: Bieri
authors.forename: M F
authors.initials: MF
authors.lastname: Mehler
authors.forename: H
authors.initials: H
authors.lastname: Xu
authors.forename: J C
authors.initials: JC
authors.lastname: Arezzo
authors.forename: J W
authors.initials: JW
authors.lastname: Pollard
authors.forename: J A
authors.initials: JA
authors.lastname: Kessler
mesh_terms: D000818:Animals; D001483:Base Sequence; D001640:Bicuculline / Q000494:pharmacology; D001921:Brain / Q000196:embryology* / Q000254:growth & development / Q000378:metabolism; D002478:Cells, Cultured; D004594:Electrophysiology; D005071:Evoked Potentials; D018756:GABA Antagonists / Q000494:pharmacology; D016236:Genes, fms; D016173:Macrophage Colony-Stimulating Factor / Q000172:deficiency / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010022:Osteopetrosis / Q000235:genetics / Q000503:physiopathology; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D018756:GABA Antagonists; D012333:RNA, Messenger; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor; D001640:Bicuculline