DEVELOPMENT AND GENETICS OF NEURAL TUBE DEFECTS

这项研究的长期目标是了解正常的 神经形成的过程，导致形成一个封闭的神经 管，整个中枢神经系统的前身，并 了解这一关键过程被破坏的机制， 神经管缺陷（NTDs）的起源。 NTD，如脊柱裂， 是人类最常见和最严重的先天畸形之一。 小鼠中的神经形成在所有实际目的上都与小鼠中的神经形成相同。 人类此外，许多遗传突变小鼠可作为 人类疾病的动物模型，这些提供了不同的 优点是它们提供了连续的和可再现的 实验材料 深入了解这种动物模型 可能最终导致人类NTD的预防或治疗。 这项研究的首要目标之一是确定细胞的模式 在正常神经形成过程中发生的细胞形状的运动和变化 在哺乳动物中。 此外，外胚层中的正常细胞命运和谱系 和中胚层将被确定。 在描述了这些过程之后 在正常小鼠中，它们将在卷曲尾突变小鼠中进行检查， 确定是否有任何被破坏和因果关系的神经管 缺损这些事件将在整个胚胎培养中使用 各种酶，荧光和逆转录病毒标记物，以跟踪 细胞的运动。 很明显，如果你阻止神经管缺陷，你会 防止由此产生的神经损伤。 然而，代替 完全预防缺陷，这是极端的临床重要性， 减少神经功能缺损。 卷曲尾突变体提供了一种 这是一个独特的机会来研究NTD对神经元的影响， 区分，以确定是否有关键时期，在此期间， 开放的神经管对神经系统的损害最大。 这将 使用几种单克隆抗体进行检查，以监测神经元 在曲尾小鼠中的分化，并将结果与正常小鼠进行比较 同窝出生的 最后，将进行各种遗传研究，以确定 卷曲尾基因的染色体定位， 连锁遗传标记 此外，还将努力寻找一个 遗传背景，这将提高的表达能力和表现力， 这种突变体，并确定其他遗传基因座，修改表达 疾病。 这些其他的基因可以提供重要的线索， NTD的原因和可能的预防方法。

The long-term objectives of this research are to understand the normal process of neurulation, which results in the formation of a closed neural tube, the precursor of the entire central nervous system, and to understand the mechanisms by which this critical process is disrupted in the genesis of neural tube defects (NTDs). NTDs, such as spina bifida, are among the most common and most severe human congenital malformations. Neurulation in mice is for all practical purposes identical to that in humans. In addition, a number of genetically mutant mice are available as animal models of the human disease, and these offer the distinct advantage that they provide a continuous and reproducible source of experimental material. A thorough understanding of such animal models could eventually lead to the prevention or treatment of human NTDs. One of the first aims of this research is to define the patterns of cell movements and changes in cell shapes that occur during normal neurulation in mammals. In addition, normal cell fates and lineages in the epiblast and mesoblast will be determined. Having characterized these processes in normal mice, they will be examined in the curly tail mutant mouse to determine if any are disrupted and causally related to the neural tube defect. These events will be studied in whole embryo cultures using a variety of enzyme, fluorescent, and retroviral markers to follow the movements of cells. It is obvious that if you prevent the neural tube defect, you will prevent the resulting neurological impairments. However, in lieu of total prevention of the defect, it is of extreme clinical importance to reduce the neurological deficits. The curly tail mutant provides a unique opportunity to examine the effects of NTDs on neuronal differentiation to determine if there are critical periods during which the open neural tube is most damaging to the nervous system. This will be examined using several monoclonal antibodies to monitor neuronal differentiation in curly tail mice and to compare the results to normal littermates. Finally, a variety of genetic studies will be conducted to determine the chromosomal location of the curly tail gene and to identify closely linked genetic markers. In addition, attempts will be made to find a genetic background that will improve the penetrance and expressivity of this mutant and to identify other genetic loci that modify the expression of the disease. These other genes could offer important clues to the causes of NTDs and possible means of prevention.