Sources of Diversity in Axon Patterning: Roles of the Many Isoforms of the Transcription Factor, Lola

过去，人们认为人类基因组有10万个甚至100万个基因，但现在我们知道，实际数字接近3万个。然而，这个中等大小的基因组必须为一个难以想象的复杂的大脑和神经系统编码蓝图。少数基因是如何决定所有这些复杂性的呢？部分答案似乎在于人们如何计算基因的数量。在果蝇中，有一种叫做“Lola”的基因，它指定神经细胞之间的连接。最近的研究表明，这个基因有20种不同的形式，这些研究暗示，这20种不同的形式可能允许这个基因完成20种不同基因的工作。此外，这20种形式似乎能够以不同的组合方式配对，这样它们就能有效地像一个由几百个基因组成的家族——然而所有基因都是由“一个”基因编码的，lola。这项提议的目标是详细测试一个基因可以完成几十个或几百个基因的工作的想法，并了解这一发现对神经系统的构建有什么影响。将测试这些不同表单中的几个表单的活动，方法是一次删除一个表单，或者删除一个表单然后添加一个不同的表单。这些形式之间的相互作用也将以类似的方式进行测试。我们对果蝇中lola基因的了解也肯定会告诉我们，人类基因组中为数不多的基因是如何以不同的组合方式协同工作，以确定人类神经系统的复杂性的。PI积极参与本科生和研究生的培训，该项目将提供丰富的研究经验机会。

It used to be thought that the human genome had 100,000 or even 1,000,000 genes, but now we know that the real number is closer to 30,000. And yet, this modest-sized genome has to encode the blueprint for a brain and nervous system of unimaginable complexity. How does a small number of genes specify all of this complexity?Part of the answer seems to be in how one counts the number of genes. In the fruit fly, there is a gene called "Lola" that specifies the connections between nerve cells. Recent studies have shown that this one gene comes in 20 different forms, and these studies hint that those 20 different forms may allow this single gene to do the work of 20 different genes. Moreover, those twenty forms seem to be able to pair up in different combinations, so that they can effectively act like a family of several hundred genes - yet all are encoded by "one" gene, lola. The goal of this proposal is to test in detail this idea that one gene can be made to do the work of dozens, or hundreds of genes, and to understand what implications that finding has for how a nervous system is built. The activities of several of these differing forms will be tested, by knocking out the forms, one at a time, or knocking out one and adding back a different one. The interactions among these forms will also be tested, in a similar way. What is learned about lola in fruit flies is certain also to tell us how the few genes in the human genome can work together in different combinations to specify the complexity of the human nervous system. The PI is actively involved in training of undergraduate and graduate students and this project will offer rich opportunities in research experience.