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 Our unpublished data, however, demonstrates that the tissue-specific deletion of three FGF receptor genes results in the loss of the telencephalon, except the dorsal midline,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。 公共卫生关系：在人类怀孕的第五周左右，新生的中枢神经系统的前部（神经板）开始表达标记胚胎大脑或端脑的特征性基因。不久之后，神经板闭合形成神经管。在这一阶段，端脑在形态学上变得明显，像一片包围着双侧脑室的膨胀的细胞。端脑主要在背侧产生新皮层和海马体，用于我们的最高认知功能，在腹侧产生基底神经节，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，即无脑畸形，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。无端脑畸形可能是前脑截短的一部分，包括更严重的无前脑畸形，其中端脑和丘脑都缺失。缺乏可用的家庭与大量的情况下，这些疾病的遗传原因的研究困难，强调的重要性，动物模型，特别是小鼠模型，在确定的遗传途径，导致端脑诱导和维护。识别这些途径将导致诊断和治疗前脑截断疾病的新策略，如先前所述的神经管缺陷。在这个建议中，使用遗传学方法在小鼠中，我们直接测试三个信号通路的功能，WNT，FGF和BMP，在端脑的初始形成。此外，通过检查这些途径的相互作用，我们发现它们之间的相互依赖性，这对理解其他组织的发育如何受到调节，增生组织中的增殖如何受到错误调节以及这些异常组织如何被新疗法靶向具有广泛的意义。