Oocyte polarity and mRNA localization in Zebrafish

 描述（由申请人提供）：最早的发育事件发生在合子基因组失活时;因此，脊椎动物的发育依赖于母体提供的基因产物。破坏编码这些必要的母体因子的基因（母体效应基因）的突变可能是致畸的或致命的。由于母亲提供的正常基因功能，母亲效应基因功能失调的女性总体上是正常的。然而，这些雌性的后代发育异常，无论其基因型如何。尽管越来越多的人认识到母体产品对脊椎动物发育和健康的重要影响，但只有少数母体效应基因通过遗传或干扰方法进行了实验评估。对于那些已经检查过的基因，很明显，母体贡献不足会导致早期胚胎死亡，或者在不太严重的情况下，发育异常。人类中类似的遗传缺陷预计会导致植入失败或在女性知道自己怀孕之前流产。10%到20%的怀孕被诊断为流产;然而，许多怀孕未被发现。根据The March of Dimes，美国妇产科医师学院，马约诊所和国家儿童健康与发展研究所的数据，当这些因素被考虑在内时，以流产告终的怀孕的实际百分比估计要高得多，占所有怀孕的40-50%。我们的长期研究目标是确定指导脊椎动物胚胎第一轴发育的遗传途径和细胞生物学事件。我们将继续在斑马鱼中使用遗传学、分子遗传学、细胞生物学和亲和纯化方法的组合 模型系统在人类中，其产物对第一个胚胎轴的特化至关重要的基因的功能突变的丧失可能会由于严重的发育异常而导致流产。此外，我们研究的卵母细胞发育方面发生在哺乳动物的胎儿发育期间;因此，这个过程在人类中是不可访问的。在模式系统中，如斑马鱼，受精和胚胎的发育发生在外部，每个产生的卵子都可以检查发育异常。因此，斑马鱼是一个强大的脊椎动物系统，研究母系控制的过程，这是很难在哺乳动物中获得，也不可能在人类中研究。值得注意的是，许多已知调节生殖系发育的基因从无脊椎动物到哺乳动物都是保守的;因此，对调节斑马鱼生殖系和胚胎发育的最早模式化事件的必需母体基因的更好理解将提供对出生缺陷，流产和不育的基础的深入了解，并将促进与人类蛋白质的比较。

 DESCRIPTION (provided by applicant):The earliest developmental events occur while the zygotic genome is inactivated; thus, vertebrate development depends on maternally supplied gene products. Mutations that disrupt the genes that encode these necessary maternal factors, maternal-effect genes, can be teratogenic or lethal. Females with dysfunctional maternal-effect genes are grossly normal, due to normal gene function supplied by their mother. However, the progeny of these females develop abnormally regardless of their genotype. Despite increasing awareness of the significant impact maternal products have on vertebrate development and health, only a few maternal-effect genes have been experimentally evaluated through genetic or by interference approaches. For those genes that have been examined, it is clear that inadequate maternal contribution results in early embryonic lethality, or in less severe cases, developmental abnormalities. Similar genetic defects in humans are expected to result in failed implantation or miscarriage before a woman knows she is pregnant. Ten to twenty percent of pregnancies that are diagnosed result in miscarriage; however, many pregnancies go undetected. When these are factored in, the actual percentage of pregnancies that end in miscarriage is estimated to be significantly higher affecting 40-50% of all pregnancies, according to The March of Dimes, The American College of Obstetricians and Gynecologists, The Mayo clinic, and the National Institutes on Child Health and Development. Our long-term research goal is to determine the genetic pathways and cell biological events that direct development of the first axis of the vertebrate embryo. We will continue to use a combination of genetic, molecular genetics, cell biological, and affinity purification approaches in the zebrafish model system. In humans, losses of function mutations in genes whose products are essential for specification of the first embryonic axis will likely cause miscarriage due to severe developmental abnormalities. Moreover, the aspects of oocyte development that we study occur during fetal development in mammals; so, this process is not accessible in humans. In model systems such as zebrafish where fertilization and development of the embryo occur externally every egg produced can be examined for developmental abnormalities. Thus, the zebrafish is a powerful vertebrate system to study maternally controlled processes that are difficult to access in mammals and not possible to study in humans. Significantly, many of the genes known to regulate germline development are conserved from invertebrates to mammals; therefore, an improved understanding of the essential maternal genes that regulate the earliest patterning events of the germline and embryonic development in zebrafish will provide insight into the basis of birth defects, miscarriage, and infertility, and will facilitate comparison with human proteins.