WNTs, FGFs, and BMPs Induce and Maintain the Telencephalon

WNT、FGF 和 BMP 诱导和维持端脑

• 批准号: 8068656
• 负责人: JEAN M HEBERT
• 金额: $ 41.09万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8068656
• 关键词: Address; Adopted; Adult; Alleles; Animal Model; Anterior; Aprosencephalies; Basal Ganglia; Bilateral; Birth; Cells; Cerebral hemisphere; Cerebrum; Data; Development; Diagnosis; Disease; Dorsal; Ectoderm; Embryo; Emotional; Exons; Family; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Genes; Genetic; Goals; Growth Factor Receptor Genes; Hippocampus (Brain); Human; Hyperplasia; Inherited; Lead; Maintenance; Mediating; Motor; Mus; Neocortex; Neural Tube Defects; Neural tube; Neuraxis; Neuroectoderm; Pathway interactions; Pattern; Phenotype; Play; Pregnancy; Prosencephalon; Proteins; Reporting; Research; Role; Signal Pathway; Signal Transduction; Somites; Staging; Telencephalon; Testing; Thalamic structure; Tissues; Undifferentiated; Zebrafish; cognitive function; in vivo; loss of function; mouse model; mutant; neural plate; neural precursor cell; neuroepithelium; precursor cell; public health relevance; relating to nervous system

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 Our unpublished data, however, demonstrates that the tissue-specific deletion of three FGF receptor genes results in the loss of the telencephalon, except the dorsal midline,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

描述（由申请人提供）：胚胎神经板由产生中枢神经系统的未分化神经前体细胞组成。在神经板的前部区域，细胞呈现端脑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部细胞采用端脑命运，以及是什么促进了它们的生存和增殖。将神经外胚层与下层外胚层分界的前神经嵴（ANR）对于诱导神经板细胞的端脑特征是必要且充分的。该脊分泌成纤维细胞生长因子 (FGF)，并且至少在斑马鱼中，还分泌由 tlc 基因编码的 Wingless-Int (WNT) 拮抗剂。 tlc 的敲低或其他 WNT 拮抗剂（axin，six3）的缺失会导致斑马鱼端脑标记物的缺失，表明低 WNT 信号传导对于端脑诱导是必需的。在小鼠中，目前尚不清楚低 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，尽管尚未有任何物种中的 FGF 信号突变体导致端脑丧失的报道。然而，我们未发表的数据表明，组织特异性删除三个 FGF 受体基因会导致除背中线之外的端脑丧失，并且 FGF 信号通过诱导和形成端脑神经上皮并维持其细胞存活来介导组织者活动。在本提案中，我们使用遗传和外植体培养方法，测试 WNT 是否调节小鼠端脑诱导，以及该通路如何与 FGF 和 BMP 通路相互作用，调节细胞命运、存活和增殖。 公共健康相关性：在人类妊娠的第五周左右，新兴中枢神经系统（神经板）的前部开始表达特征性标记胚胎大脑或端脑的基因。不久之后，神经板自行闭合形成神经管。在这个阶段，端脑在形态上变得明显为双侧脑室周围膨胀的细胞片。端脑主要产生背侧的新皮质和海马体，用于最高认知功能，以及腹侧的基底神经节，用于运动协调和情感功能。在人类中，出生时端脑衍生物的缺失（无脑畸形）在某些情况下被怀疑是一种遗传性隐性疾病，但突变基因尚不清楚。无脑畸形可能是一系列前脑截断的一部分，包括更严重的前脑畸形，其中端脑和丘脑均缺失。由于缺乏具有大量病例的可用家族，使得对这些疾病的遗传原因的研究变得困难，这强调了动物模型，特别是小鼠模型，在确定导致端脑诱导和维持的遗传途径方面的重要性。识别这些途径将带来诊断和治疗前脑截断疾病的新策略，正如之前针对神经管缺陷所描述的那样。在本提案中，我们利用小鼠遗传方法，直接测试了 WNT、FGF 和 BMP 三种信号通路在端脑初始形成过程中的功能。此外，通过检查这些途径的相互作用，我们正在揭示它们之间的相互依赖性，这对于理解其他组织的发育如何被调节、增生组织的增殖如何被错误调节以及如何用新疗法针对这些异常组织具有广泛的意义。 。