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。 与公共卫生相关：在人类怀孕约第五周时，新出现的中枢神经系统的前部(神经板)开始表达具有胚胎大脑或端脑特征的基因。不久之后，神经板自行关闭，形成神经管。在这个阶段，端脑在形态上变得明显，表现为围绕着双侧脑室的一层膨大的细胞。端脑主要产生背侧的新大脑皮层和海马体，我们用来实现最高的认知功能，以及基底节腹侧，我们用它来运动协调和情感功能。在人类中，出生时缺乏端脑衍生物，即小脑症，在某些情况下被怀疑是遗传性隐性疾病，但突变基因尚不清楚。无脑畸形可能是前脑连续截断的一部分，包括更严重的端脑和丘脑均缺失的无脑畸形。缺乏具有大量病例的现有家系使得对这些疾病的遗传原因的研究变得困难，这突显了动物模型，特别是小鼠模型在确定导致端脑诱导和维持的遗传路径方面的重要性。识别这些通路将导致诊断和治疗前脑截断障碍的新策略，就像之前针对神经管缺陷所描述的那样。在这个方案中，我们使用小鼠的遗传学方法，直接测试三个信号通路，WNT，成纤维细胞生长因子和BMP，在端脑的初始形成中的功能。此外，通过研究这些途径的相互作用，我们正在揭示它们之间的相互依赖关系，这对于理解其他组织的发育是如何调控的，增生性组织中的增殖如何可能被错误调控，以及如何通过新的治疗针对这些异常组织具有广泛的意义。

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 Our unpublished data, however, demonstrates that the tissue-specific deletion of three FGF receptor genes results in the loss of the telencephalon, except the dorsal midline,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. PUBLIC HEALTH RELEVANCE: At about the fifth week of gestation in humans, the anterior part of the emerging central nervous system (the neural plate) begins to express genes that characteristically mark the embryonic cerebrum, or telencephalon. Shortly after, the neural plate closes on itself to form the neural tube. At this stage the telencephalon becomes morphologically apparent as an inflated sheet of cells surrounding bilateral ventricles. The telencephalon gives rise primarily to the neocortex and hippocampus dorsally, which we use for our highest cognitive functions, and the basal ganglia ventrally, which we use for motor coordination and emotional functions. In humans, the absence of telencephalic derivatives at birth, atelencephaly, is suspected in some cases of being an inherited recessive disorder, but the mutant genes are unknown. Atelencephaly may be part of a continuous spectrum of forebrain truncations including the more severe aprosencephaly in which both telencephalon and thalamus are missing. The lack of available families with significant numbers of cases makes research into the genetic causes of these disorders difficult, underscoring the importance of animal models, particularly mouse models, in identifying the genetic pathways that lead to telencephalic induction and maintenance. Identifying these pathways will lead to new strategies for diagnosing and treating forebrain truncation disorders, as previously described for neural tube defects. In this proposal, using a genetic approach in the mouse, we directly test the function of three signaling pathways, WNT, FGF, and BMP, in the initial formation of the telencephalon. Moreover, by examining the interaction of these pathways, we are uncovering interdependencies among them which have broad implications for understanding how development of other tissues is regulated, how proliferation in hyperplastic tissues can be misregulated, and how these abnormal tissues can be targeted with new therapies.