Molecular Basis of Neural Development in Xenopus

爪蟾神经发育的分子基础

• 批准号: 7663668
• 负责人: ALI H BRIVANLOU
• 金额: $ 49.03万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7663668
• 关键词: Address; Adult; BMP15 gene; BMP4; Binding; Binding Proteins; Biochemical; Biological; Cells; Complex; Disease; Dominant-Negative Mutation; Dorsal; Ectoderm; Embryo; Embryology; Embryonic Development; Embryonic Induction; Epidermis; Failure; Family; Funding; Genes; Germ Layers; Growth Factor; Head; Homeostasis; Human; Infertility; Knowledge; Laboratories; Length; Life; Ligands; Link; MAP3K7 gene; Malignant Neoplasms; Mediating; Menopause; Mesoderm; Mitogen-Activated Protein Kinases; Molecular; Mutation; Nerve Block; Ovarian; Pathway interactions; Pattern; Phosphotransferases; Proteins; Repression; Role; Signal Pathway; Signal Transduction; Tail; Tissues; Transducers; Work; Xenopus; Xenopus laevis; base; cell type; developmental disease; early onset; gastrulation; human MAP3K7IP1 protein; in vivo; inhibitor/antagonist; loss of function; member; neural model; neural plate; neurodevelopment; novel; relating to nervous system; research study

The ultimate objective of my laboratory is to decipher the molecular basis of neural/epidermal induction and patterning in the vertebrate embryo. Our previous work has shown that one of the earliest steps in the determination of neural fate requires inhibition of BMP/GDF signaling. BMP/GDF ligands belong to the TGF_ signaling pathway. This established the concept of the "default model" of neural induction. The inhibition of BMP/GDF signaling occurs in vivo in the dorsal ectoderm during gastrulation, and is mediated by secreted factors emanating from the organizer (dorsal mesoderm). As a direct result of this inhibition, dorsal ectoderm forms neural tissue. In the ventral ectoderm, where the BMP/GDF pathway is not inhibited, signaling by these factors via signal transducers Smad1/5/8 leads to the induction of epidermis. In this repackaged competitive renewal, I propose to continue our efforts in dissecting the TGF_ signaling pathways that underlie ectodermal patterning at the molecular, cellular and embryological level by focusing on the characterization of an unexpected inhibitor of the pathway, that was discovered during our previous round of funding: TAB3 (TAK1- Binding-protein-3). TAK1 (TGFb-Activated-Kinase-1), and TAB3 transduce BMP/GDF signal in Smad independent manner, and thus links the BMP pathway to the MAP kinase pathway. Two specific aims are proposed. The first targets the characterization of binding partners of TAB3, which transduces BMP signals in a Smad independent manner. The second specific aim, targets the characterization of the cellular and embryological functions of TAB3-binding partners. TAB3 links the BMP pathway to the MAP kinase pathway. As the BMP pathway is involved in large numbers of biological activities, an in-depth molecular understanding of the pathway will have a direct impact on many different fields in addition to molecular embryology.

我实验室的最终目标是破译脊椎动物胚胎中神经/表皮诱导和模式的分子基础。我们以前的工作表明，确定神经命运的最早步骤之一需要抑制BMP/GDF信号传导。 BMP/GDF配体属于TGF_信号通路。这确立了神经诱导的“默认模型”的概念。 BMP/GDF信号的抑制作用在胃术中的背外胚层中发生在体内，并由组织者发出的分泌因子介导（背部中胚层）。作为这种抑制作用的直接结果，背外胚层形成神经组织。在腹侧外侧，其中BMP/GDF途径没有抑制，这些因素通过信号传感器SMAD1/5/8信号导致表皮诱导。在这种重新包装的竞争性更新中，我建议继续努力剖析TGF_信号传导途径，这些信号传导途径是分子，细胞和胚胎学水平上的外胚层模式的基础，该途径专注于对途径的意外抑制剂的表征，这些途径是在上一轮资金中发现的：Tab3（Tab3 Binding-Binding-bitting-pote-pote-prote-prote-3）。以SMAD独立的方式将TAK1（TGFB激活-1-激酶-1）和TAB3传递BMP/GDF信号，从而将BMP途径连接到MAP激酶途径。提出了两个具体目标。第一个目标是TAB3的结合伙伴的表征，该伙伴以SMAD独立的方式传递BMP信号。第二个特定目的是针对TAB3结合伴侣的细胞和胚胎学功能的表征。 TAB3将BMP途径链接到MAP激酶途径。由于BMP途径参与了大量生物学活性，因此对途径的深入分子理解将直接影响除了分子胚胎学之外，还将对许多不同的领域产生影响。