Analysis of cytokine signaling and regulation of stem cells.

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Development of multicellular organs is regulated by various external signals and intrinsic cues. This project is amied to understand molecular regulation of organ development, in particular brain development, by focusing on cytokine signaling. The interleukin-6(IL-6) family of cytokines, i.e. IL-6, IL-11, leukemia inhibitory factor(LIF), ciliary neurotrophic factor(CNTF), oncostatin M(OSM), and cardiotrophin-1(CT-1), share gp130 as a receptor component critical for signal transduction. We have found that signals from gp130 and bone morphogenetic protein(BMP) receptors act in synergy on fetal brain neural progenitor cells to induce astrocyte differentiation. For instance, LIF and BMP2 synergistically induce astrocytes in cultured neuroepithelial cells. The molecular basis proposed by us is that respective downstream transcription factors, STAT3 and Smads, form a complex bridged by a transcriptional coactivator p300. Another finding is that BMP2 inhibits neurogenesis from neural progenitor cells by upregulating expression of negative helix-loop-helix(HLH) factors, Id1, Id3 and Hes-5, which are capable of inhibiting transcriptional activity of neurogenic HLH transcription factors, Mash1 and Neurogenin. We have also identified several novel genes that are likely to regulate brain development : (1)Tbr-2 is a new member of the T-box containing gene family which is expressed predominantly expressed in the developing brain. (2)Lhx6.1 is a molecule very close to Lhx6 and shows obvious expression in olfactory bulb, medial ganglionic eminenee, arcuate nucleus in mouse fetal brain. (3)NDRP is a novel molecule expressed predominantly in developing retina, olfactory bulb and dorsal root ganglion.