Identification of genes important in myeloid and haemopoietic development by genetic screening in zebrafish

斑马鱼已经成为发育遗传学中一个强大的实验模型。其有利的属性包括其生殖生物学，胚胎的光学透明度，以及胚胎用于实验程序的可及性。国外的研究已经发现了1500多个因约500个基因的诱导突变而患有遗传性疾病的斑马鱼品系。这些斑马鱼中有许多具有意想不到的精确性的异常，并导致具有新的专门功能的新基因。大约有50种突变斑马鱼品系的红细胞发育受到干扰--这很容易识别，因为胚胎的透明度使得血液的缺乏很容易被发现。我们的新研究主要目的是恢复突变斑马鱼与障碍的白色血细胞形成。我们已经确定了识别斑马鱼白色血细胞形成失败的方法，并将采用这些方法在称为遗传筛选的过程中寻找专门影响白色血细胞发育的遗传性疾病。将系统地筛选具有不同随机突变基因组的鱼类，以识别那些具有异常白色血细胞发育的鱼类。我们已经测试了我们的方法，并确定了几个影响白色血细胞发育的突变体。一旦这些新的鱼类品种被确定，我们将通过基因定位和定位克隆在几个最有趣的品种中找到导致异常的遗传病变。因此，在筛选中鉴定的突变斑马鱼最终将导致发现在白色血细胞生长和发育中重要的新基因。鱼本身将提供见解的原因先天性疾病的白色血细胞。由于许多参与早期发育的基因在癌症中也很重要，我们相信新发现的基因也将有助于了解白血病中白色血细胞异常生长的原因。

Zebrafish have emerged as a powerful experimental model in developmental genetics. Their favourable attributes include their reproductive biology, the optical clarity of embryos, and the accessibility of embryos for experimental procedures. Previous studies overseas have recovered over 1500 strains of zebrafish with inherited diseases due to induced mutations in about 500 genes. Many of these zebrafish have abnormalities of unexpected precision and are leading to new genes with novel specialized functions. About 50 mutant zebrafish strains exist in which red blood cell development is perturbed - this was easily recognized because the transparency of embryos enabled lack of blood be easily seen. Our new studies aim primarily to recover mutant zebrafish with disorders of white blood cell formation. We have identified methods to recognize failure of white blood cell formation in zebrafish, and will employ these methods to look for inherited disorders that specifically affect white blood cell development in a process called genetic screening. Fish with different sets of randomly mutated genes will be systematically screened to identify those with abnormal white blood cell development. We have tested our approach and identified several mutants affecting white blood cell development. Once these new strains of fish are identified, we will find the genetic lesion responsible for the abnormality in several of the most interesting strains by gene mapping and positional cloning. Hence, the mutant zebrafish identified in the screen will eventually lead to the discovery of new genes important in white blood cell growth and development. The fish themselves will provide insights into the causes of congenital diseases of white blood cells. Since many genes involved in early development are also important in cancer, we believe that newly identified genes will also help understand the causes of abnormal growth of white blood cells in leukaemia.