A mutagenesis screen to identify novel genes required for late developmental processes in Xenopus tropicalis

用于鉴定热带爪蟾后期发育过程所需新基因的诱变筛选

• 批准号: 134410021
• 负责人: Dr. Isabelle Philipp
• 金额: --
• 依托单位: Department of Molecular and Cell Biology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2011-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/134410021?language=en
• 关键词: mutagenesis; screen; identify; novel; genes

Inherited defects in cardiogenesis are the main cause of human birth defects. In addition, abnormal adult hearts are the most common cause of disease and mortality in the western world. The current therapeutic modalities and an understanding of the genes involved in heart development are limited. A better understanding of the genetic pathways that affect heart development is required to advance treatment possibilities. Random mutagenesis is a powerful strategy that allows identification of novel genes responsible for developmental processes in vertebrates. As the transcriptional networks regulating heart development are highly conserved between all organisms, genetic screening in the frog Xenopus tropicalis is as a model organism is an excellent strategy to enable identification of novel genes. One mutant blimpy, that exhibits a developmental defect of the heart, is of particular interest. In blimpy-/- mutants the very early heart development appears normal, but during late linear heart tube formation the endocardium fails to line the myocardium and remains aggregated in the center of the forming heart tube. These mutant hearts also fail to loop. blimpy-/- mutants also show impaired expression of lymphatic marker genes and a disrupted vascular network, which may be an independent phenotype, or secondary to the primary defect in heart formation. Genetic mapping has positioned this mutation on Chromosome 4 with its closest genetic markers at 0.5 centimorgans (cM) and 0.6 cM respectively. This region defines a physical distance of 600 kb containing 6 described and 7 unannotated genes that are conserved in mammals (Joint Genome Institute).

心脏发生的遗传缺陷是人类出生缺陷的主要原因。 此外，在西方世界，成人心脏异常是疾病和死亡的最常见原因。 目前的治疗方式和对心脏发育相关基因的理解是有限的。需要更好地了解影响心脏发育的遗传途径，以提高治疗的可能性。 随机诱变是一种强有力的策略，可以识别负责脊椎动物发育过程的新基因。 由于调节心脏发育的转录网络在所有生物体之间是高度保守的，因此在青蛙热带爪蟾（Xenopus tropicalis）中进行遗传筛选作为模式生物是能够鉴定新基因的极好策略。 一种表现出心脏发育缺陷的突变体blipsoid特别令人感兴趣。 在blibrary-/-突变体中，非常早期的心脏发育似乎是正常的，但在晚期线性心管形成期间，内皮细胞不能衬在心肌上，并且仍然聚集在形成的心管的中心。 这些突变的心脏也无法循环。 Blixin-/-突变体还显示淋巴标记基因表达受损和血管网络破坏，这可能是一种独立的表型，或继发于心脏形成中的原发性缺陷。遗传作图已将该突变定位在4号染色体上，其最接近的遗传标记分别为0.5厘摩（cM）和0.6 cM。 该区域定义了600 kb的物理距离，包含6个已描述的和7个未注释的哺乳动物中保守的基因（联合基因组研究所）。