In Vivo Analysis of TrkB Signaling During Sympathetic Nervous System Development and Neuroblastoma Pathogenesis

 描述(申请人提供)：协调脊椎动物周围神经系统模式的分子和细胞相互作用尚未完全阐明。从神经管中剥离后，形成交感神经节椎链的主干神经脊细胞向腹侧迁移到背主动脉附近，在那里聚集和凝聚，形成由分化的交感神经元和前体细胞组成的初级交感神经节链。神经脊细胞不能正确迁移和分化可能会导致出生缺陷并导致神经母细胞瘤，这是一种儿科肿瘤。指由神经脊的交感-肾上腺谱系产生的外周神经系统。不幸的是，缺乏关于交感神经系统正常发育的信息，以及信号的错误调节如何将正常的神经母细胞转化为神经母细胞瘤，严重限制了神经母细胞瘤的早期发现和治疗，使这种疾病在婴儿中往往是致命的。我们建议使用最先进的活体动物胚胎成像技术来研究交感神经系统发育和神经母细胞瘤的发病机制。我们发现了TrkB信号在交感神经发生中的一个新的作用，最近引人注目的是，它与侵袭性神经母细胞瘤有关。我们假设TrkB信号在交感神经过程中调节神经脊的可塑性和侵袭能力 系统发育处于从正常神经母细胞向神经母细胞瘤早期转化的关键时期。为了验证这一假说，我们将确定TrkB信号在交感神经系统发育中的功能作用，并建立神经母细胞瘤发病机制的鹌鹑胚胎模型。我们实验室首创的一项技术是，利用鹌鹑胚胎进行移植，并对单个人类神经母细胞瘤细胞行为进行可视化。我们最近发现，人神经母细胞瘤细胞移植到禽类胚胎中后，沿着宿主神经脊通路，不会形成肿瘤。该提案的成功将通过提供以下关键信息对神经发育和神经母细胞瘤癌症产生直接影响：(I)TrkB信号在交感神经发生和从正常神经母细胞到神经母细胞瘤的早期转变过程中的体内作用的关键信息；(Ii)快速检测神经母细胞瘤细胞的可塑性和侵袭性以及对潜在抑制剂的反应的体内模型。

 DESCRIPTION (provided by applicant): The molecular and cellular interactions that orchestrate the patterning of the vertebrate peripheral nervous system have yet to be fully elucidated. Upon delamination from the neural tube, trunk neural crest cells destined to form the vertebral chain of sympathetic ganglia migrate ventrally to the vicinity of the dorsal aorta where they aggregate and condense to form the primary chain of sympathetic ganglia composed of differentiated sympathetic neurons and precursor cells. Failure of the neural crest cells to properly migrate and differentiate may result in birth defects and lead to neuroblastoma, a pediatric tumor. of the peripheral nervous system that arises from sympatho-adrenal lineages of the neural crest. Unfortunately, the lack of information about normal development of the sympathetic nervous system and how mis-regulation of signals transform the normal neuroblast to neuroblastoma has severely limited early neuroblastoma detection and treatment, making this disease often fatal in infants. We propose to study sympathetic nervous system development and neuroblastoma pathogenesis using state- of-the-art in vivo imaging in living avian embryos. We discovered a novel role for TrkB signaling during sympathetic neurogenesis, which strikingly has recently been associated with aggressive neuroblastomas. We hypothesize that TrkB signals regulate the plasticity and invasive ability of the neural crest during sympathetic nervous system development at a critical time period when the early transformation from normal neuroblast to neuroblastoma occurs. To test this hypothesis we will determine the functional role of TrkB signaling in sympathetic nervous system development and develop a quail embryo model for neuroblastoma pathogenesis. Quail embryos allow transplantation and visualization of individual human neuroblastoma cell behaviors, a technique pioneered in our laboratory. We recently discovered that human neuroblastoma cells transplanted into the avian embryo follow host neural crest pathways and do not form tumors. The success of this proposal will have a direct impact on neural development and neuroblastoma cancer by providing: (i) critical information on the in vivo role of TrkB signaling during sympathetic neurogenesis and in the early transition from normal neuroblast to neuroblastoma; (ii) an in vivo model to rapidly assay the plasticity and invasiveness of neuroblastoma cells and response to potential inhibitors.