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 Our unpublished data, however, demonstrates that the tissue-specific deletion of three FGF receptor genes results in the loss of the telencephalon, except the dorsal midline,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，这些细胞引起中枢神经系统。在神经板的前部区域，细胞假设尾脑命运，并最终产生成年脑半球。这项研究的目的是了解为什么这些前细胞会采用尾脑命运以及促进其生存和增殖的原因。划定基础外胚层神经胚层的前神经脊（ANR）是必要的，足以诱导脑肾上腺素特征。该脊分泌成纤维细胞生长因子（FGFS），至少在斑马鱼中，是由TLC基因编码的无翼（Wnt）拮抗剂。 TLC的敲低或其他Wnt拮抗剂的丧失（Axin，SIX3）导致斑马鱼中脑脑标记的损失，这表明触发脑诱导是必需的低Wnt信号传导。在小鼠中，尚不清楚尾脑诱导是否需要低Wnt信号传导。 FGFS也可能在诱导脑脑瘤中发挥作用，尽管尚未据报道任何物种中的FGF信号突变体导致脑脑脑丧失。然而，我们未发表的数据表明，除背中线外，三个FGF受体基因的组织特异性缺失导致远科脑的丧失，并且FGF信号通过诱导和构成触发脑脑神经上皮的诱导和构图来介导组织者的活性，并维持其细胞。在此提案中，使用遗传和外植体培养方法，我们测试WNT是否调节小鼠中的端脑诱导以及该途径如何与FGF和BMP途径相互作用，以调节细胞命运，存活和增殖。 公共卫生相关性：大约在人类妊娠的第五周，新兴中枢神经系统的前部（神经板）开始表达具有标志着胚胎大脑或端脑特征的基因。此后不久，神经板自身关闭以形成神经管。在此阶段，尾脑在形态上变得很明显，因为双侧心室周围的细胞膨胀。尾脑主要引起了新皮层和外侧海马，我们用于最高的认知功能，而基底神经节则用于运动配位和情感功能。在人类中，在某些情况下是遗传性隐性疾病，但突变基因尚不清楚。腹腔胸膜可能是前脑截断连续频谱的一部分，包括远期脑脑和丘脑均缺失的更严重的整脑。缺乏有大量病例的可用家族使研究这些疾病的遗传原因很难进行研究，强调了动物模型，尤其是小鼠模型的重要性，尤其是小鼠模型，在识别导致端脑诱导和维持的遗传途径方面。如前所述，确定这些途径将导致新的策略来诊断和治疗前脑截断障碍，如先前针对神经管缺陷所述。在此提案中，使用小鼠中的遗传方法，我们直接测试了端脑的初始形成中三个信号通路，Wnt，FGF和BMP的功能。此外，通过检查这些途径的相互作用，我们发现了它们之间的相互依赖性，这些相互依存关系对了解其他组织的发展如何受到调节，如何误导增生组织中的增殖以及如何将这些异常组织靶向新疗法。