CSF-1 DEFICIENCY IN MICE RESULTS IN ABNORMAL BRAIN-DEVELOPMENT

Colony stimulating factor-1 (CSF-1) was initially identified as a grow th factor for mononuclear phagocytes, This study examines the role of CSF-1 in the development of the central nervous system (CNS), CSF-1 tr eatment of neurons cultured from embryonic brain promoted survival and process outgrowth in a dose-dependent manner, By contrast, CSF-1 trea tment of neurons cultured from the osteopetrotic (op/op) mouse, a null mutant for CSF-1, promoted significantly less process outgrowth, sugg esting that there are neural abnormalities in op/op animals. Nuclease protection assays were used to determine whether CSF-1 and its recepto r are expressed at times appropriate to regulate neural development, B oth CSF-1 and its receptor are expressed in developing mouse brain, wi th a unique pattern of CSF-1 mRNA splice variant expression encoding s ecreted, and not membrane-bound, growth factor, To determine whether b rain function is altered by null mutation of CSF-1, op/op mice were ex amined using electrophysiologic assays, Brainstem auditory and visual evoked potentials were both abnormal in op/op mice. Further, intracort ical recordings revealed aberrant neuronal function within visual cort ex 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 eff ects 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 develop ment.