WNTs, FGFs, and BMPs Induce and Maintain the Telencephalon

描述(申请人提供)：胚胎神经板由形成中枢神经系统的未分化神经前体细胞组成。在神经板的前部，细胞承担了端脑的命运，最终形成了成人的大脑半球。这项研究的目标是了解为什么这些前部细胞采用端脑命运，以及是什么促进了它们的存活和增殖。区分神经外胚层和下外胚层的前神经脊(ANR)是诱导神经板细胞具有端脑特征的必要条件和充分条件。这种脊会分泌成纤维细胞生长因子(FGFs)，至少在斑马鱼中，会分泌一种由TLC基因编码的WNT拮抗剂。TLC的敲除或其他WNT拮抗剂(Axin，Six3)的丢失会导致斑马鱼端脑标志物的丢失，这表明低WNT信号是端脑诱导所必需的。在小鼠中，目前还不清楚低WNT信号是否是端脑诱导所必需的。FGFs也可能在端脑的诱导中发挥作用，尽管目前还没有任何物种中的FGFs信号突变导致端脑丢失的报道。然而，我们未发表的数据表明，组织特异性的三个成纤维细胞生长因子受体基因的缺失导致了除中线背侧外的端脑的丢失，而且成纤维细胞生长因子信号通过诱导端脑神经上皮细胞的形成和维持其细胞的存活来调节组织者的活动。在这个方案中，我们使用遗传和外植体培养的方法，测试WNTs是否调节小鼠端脑的诱导，以及这一途径如何与成纤维细胞生长因子和骨形态发生蛋白途径在调节细胞命运、存活和增殖方面相互作用。

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 Our unpublished data, however, demonstrates that the tissue-specific deletion of three FGF receptor genes results in the loss of the telencephalon, except the dorsal midline,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.