WNTs, FGFs, and BMPs Induce and Maintain the Telencephalon

描述（由申请人提供）：胚胎神经板由未分化的神经前体细胞组成，这些细胞产生中枢神经系统。在神经板的前部区域，细胞承担端脑的命运，并最终产生成人大脑半球。这项研究的目的是了解为什么这些前细胞采用端脑的命运，是什么促进了它们的生存和增殖。前神经嵴（ANR）将神经外胚层与下层外胚层区分开来，是诱导神经板细胞端脑特征的必要和充分条件。该脊分泌成纤维细胞生长因子（FGF），并且至少在斑马鱼中，分泌由tlc基因编码的无翅Int（WNT）拮抗剂。敲除TLC或其他WNT拮抗剂（axin，six3）的损失导致斑马鱼端脑标记物的损失，表明低WNT信号传导是端脑诱导所必需的。在小鼠中，尚不清楚低WNT信号传导是否是端脑诱导所必需的。FGF也可能在诱导端脑中发挥作用，尽管尚未报道任何物种中的FGF信号转导突变体导致端脑的丧失。然而，我们未发表的数据表明，三个FGF受体基因的组织特异性缺失导致端脑的损失，除了背中线，FGF信号传导介导的组织者活动诱导和图案化的端脑神经上皮细胞和维持其细胞存活。在这个建议中，使用遗传和外植体培养方法，我们测试WNTs是否调节小鼠端脑诱导，以及该途径如何与FGF和BMP途径相互作用，调节细胞命运，存活和增殖。

DESCRIPTION (provided by applicant): The embryonic neural plate is comprised of undifferentiated neural precursor cells that give rise to the central nervous system. In the anterior region of the neural plate, cells assume a telencephalic fate and eventually generate the adult cerebral hemispheres. The goal of this research is to understand why these anterior cells adopt a telencephalic fate and what promotes their survival and proliferation. The anterior neural ridge (ANR) that demarcates neuroectoderm from underlying ectoderm is necessary and sufficient to induce telencephalic character to neural plate cells. This ridge secretes Fibroblast Growth Factors (FGFs) and, at least in zebrafish, a Wingless-Int (WNT) antagonist encoded by the tlc gene. Knockdown of tlc or loss of other WNT antagonists (axin, six3) results in loss of telencephalic markers in zebrafish, indicating that low WNT signaling is necessary for telencephalon induction. In mice, it remains unclear if low WNT signaling is necessary for telencephalon induction. FGFs may also play a role in inducing the telencephalon, although no FGF signaling mutant in any species has yet been reported to result in the loss of the telencephalon. Our unpublished data, however, demonstrates that the tissue-specific deletion of three FGF receptor genes results in the loss of the telencephalon, except the dorsal midline, and that FGF signaling mediates organizer activity by inducing and patterning the telencephalic neuroepithelium and maintaining its cells alive. In this proposal, using genetic and explant culture approaches, we test whether WNTs regulate telencephalon induction in the mouse and how this pathway interacts with the FGF and BMP pathways in regulating cell fate, survival, and proliferation.