Analysis of cytokine signaling and regulation of stem cells.

多细胞器官的发育受多种外部信号和内在信号的调控。该项目旨在通过关注细胞因子信号传导来了解器官发育，特别是大脑发育的分子调控。白细胞介素-6（IL-6）家族细胞因子，即IL-6、IL-11、白血病抑制因子（LIF）、纤毛神经营养因子（CNTF）、抑癌素M（OSM）和心肌营养因子-1(CT-1)，共享gp130作为信号转导的关键受体成分。我们发现gp130和骨形态发生蛋白（BMP）受体的信号协同作用于胎儿脑神经祖细胞，诱导星形胶质细胞分化。例如，LIF和BMP2在培养的神经上皮细胞中协同诱导星形胶质细胞。我们提出的分子基础是，各自的下游转录因子STAT3和Smads形成了一个由转录辅激活子p300桥接的复合体。另一个发现是BMP2通过上调负螺旋-环-螺旋（HLH）因子Id1、Id3和Hes-5的表达来抑制神经源性HLH转录因子Mash1和Neurogenin的转录活性，从而抑制神经祖细胞的神经发生。我们还发现了几个可能调节大脑发育的新基因：(1)Tbr-2是T-box基因家族的新成员，主要在发育中的大脑中表达。(2)Lhx6.1是一个与Lhx6非常接近的分子，在小鼠胎脑嗅球、内侧神经节突起、弓形核中有明显表达。(3)NDRP是一个主要表达于视网膜、嗅球和背根神经节发育的新分子。

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.