Expression and function of hematopoietic cytokines in developing brain

Abstract

The ontogeny of the nervous system, like that of the immune system, is regulated in part by soluble peptides known as growth factors. In this study, we have investigated the role of hematopoietic cytokines, which include interleukins (IL) and colony stimulating factors (CSF), in brain development. The parallels between hematopoiesis and neuropoiesis suggested that some of these factors might function in central nervous system (CNS) development, and we have identified two such cytokines, CSF-1 and IL7.;Electrophysiologic studies of CSF-1 mutant osteopetrosis (op/op) mice demonstrate abnormal evoked potentials in response to sensory stimuli, with specific impairment of {dollar}\gamma{dollar}-aminobutyric acid (GABA)-related circuitry in cerebral cortex. CSF-1 treatment of cells cultured from embryonic brain promotes neurite outgrowth. Similarly, IL7 treatment of embryonic brain cultures directly increases neuronal survival and neurite outgrowth. IL7 also induces neuronal differentiation of subventricular zone progenitor cells. Phosphorylation of p59{dollar}\sp{lcub}fyn{rcub}{dollar} is activated, and the expression of c-myc mRNA upregulated, by IL7 in cultured neurons. Finally, mRNAs encoding CSF-1, IL7, and their respective receptors are expressed in vivo in developing brain. The effects of CSF-1 and IL7 on embryonic neural cells together with developmentally appropriate expression of ligand.;Expression studies of the Jak kinases and STAT transcription factors, which together constitute the primary signal transduction pathway for most cytokines, reveals that certain Jaks and STATs display ubiquitous expression in brain. Jak3, which has been reported to be lymphoid-specific, is found in brain as well, with a developmental pattern peaking postnatally. STAT3 manifests a cellular distribution similar to that of Jak3, with expression in cultured microglia and astrocytes. Both Jaks and STATs are expressed in the peripheral nervous system, and Jak3 is expressed in Schwann cells but not neurons. Our findings that these signal transduction elements are expressed in brain development further testify that cytokines may be important trophic factors in neuropoiesis.