Cytokines in brain development and function

Although studies of hemopoietins in neural development are still in their infancy, there is already significant evidence that these cytokines exhibit cellular and developmental response profiles similar to those found during hematolymphopoiesis. Thus, during neurogenesis, hemopoietins exhibit complementary and combinatorial interactions, integrated signaling within a single lineage mediated by members of factor subclasses that possess common receptor subunits, expression and activation of analogous intracellular signaling molecules and pathways, and actions at similar developmental stages and through related cellular actions (128-130). These experimental observations suggest that many of the regulatory mechanisms utilized by the hemopoietins during sequential stages of hematopoietic and immune system development will have significant parallels to those active during neurogenesis. During early phases of CNS stem and multipotent progenitor cell development, there is already preliminary evidence that early- and intermediate-acting hemopoietins may exert complementary and cooperative actions on progenitor cell proliferation and survival in association with early-acting CNS cytokines (e.g., EGF, bFGF) (11, 12). Individual hemopoietins may also exert several distinct cellular actions during the development of a single CNS lineage (e.g., proliferation, survival, differentiation), suggesting that these cytokines are capable of activating multiple signaling pathways (3, 25, 27). Evidence from the hematopoietic literature has also shown that synergistic interactions between hemopoietin subgroups may be factor specific for a defined progenitor cells stage within a single lineage, and preliminary observations using cultured neural embryonic progenitor species have revealed similar patterns of developmental signaling (3, 25, 131, 132). Finally, experimental studies during early stages of hematopoiesis have shown that cell cycle regulation mediated by hemopoietin cooperativity may involve the interplay of cell cycle regulatory molecules and the levels of retinoblastoma protein phosphorylation (133). Previous studies using homozygous null mutations of the retinoblastoma gene have demonstrated the particular importance of this protein for intermediate stages of CNS neurogenesis, and thus suggest that detailed analysis of selected cell cycle regulatory proteins will be crucial for defining the role of cell cycle transitions in neural lineage commitment and in early stages of cellular differentiation and viability (134-136). Although many apparent similarities exist between hematolymphopoiesis and neurogenesis, there are also obvious molecular and functional differences between the two developmental systems that mandate distinctive future experimental approaches (137). A hallmark of neurogenesis is the development of electrical excitability and the establishment of synaptic and other functional connections between evolving neural lineage species. Preliminary evidence shows that the sequential expression of specific ligand-gated and ionic channels may be essential for the proper maturation of evolving neuroblasts and for the organization of membrane conductance patterns and that these molecular processes are regulated by specific hemopoietins (103). Further, integrated aspects of synaptogenesis, synaptic terminal organization, real- time modulation, and activity-dependent cellular morphogenesis may also each be orchestrated by distinct subsets of hemopoietins (3, 138). The analysis of these 'neural-specific' cellular functions may also reveal new and interesting areas of commonality between neurogenesis and hematolymphopoiesis. In summary, these cumulative experimental observations have already demonstrated that four helix-loop bundle cytokines have a diverse spectrum of cellular actions during neural development that rival and often exceed those of the traditional neurotrophins and even the rapidly expanding TGFβ superfamily. These cytokines are involved in multiple stages of brain and peripheral nervous system lineage restriction, commitment, progenitor cell proliferation, survival, and graded stages of cellular differentiation.