Mechanisms that induce and regulate gametogenic differentiation

我实验室的研究重点是了解细胞是如何决定生长和分裂，还是停止分裂并分化成专门的组织，如有性生殖所需的精子和卵细胞。这个过程很难在人类身上进行研究，所以我们使用了一种模式生物，出芽酵母。当营养被剥夺时，酵母细胞停止分裂，并开始一个类似于人类精子形成的过程，然而，形成的不是精子，而是孢子。为了完成这一过程，细胞必须“关闭”许多生长和细胞分裂所需的基因，同时“打开”一整套全新的基因，这些基因编码从增殖细胞转化为孢子所需的蛋白质。我们发现控制减数分裂特异性基因表达的蛋白在减数分裂和孢子形成过程中被磷酸盐修饰，这些修饰对它们的功能有巨大的影响。抑制减数分裂特异性基因的蛋白质失活，而诱导减数分裂特异性基因的蛋白质通过这种修饰过程被激活。我们已经确定了一个减数分裂特异性蛋白激酶（Ime2），我们怀疑它负责磷酸化控制减数分裂特异性基因的转录因子。我们正在使用一系列遗传生化方法来确定磷酸化如何影响控制减数分裂特异性基因的转录激活因子和抑制因子的特性。这项研究旨在了解一组减数分裂特异性基因是如何被调控的。我们特别关注这些基因在生长过程中是如何被抑制的，以及在减数分裂和产孢过程中，抑制因子发生了什么变化来激活这些基因。通过我们对酵母的研究，我们已经确定了几种在孢子形成过程中起重要作用的蛋白质；其中一些与配子形成所需的人类蛋白质非常相似。这个研究项目将增加我们对调节基因表达的基本生物化学的理解，并将为有性生殖所需的配子形成的控制提供见解。

Research in my lab is focused on understanding how cells make the decision to grow and divide or to stop dividing and differentiate into specialized tissues such as the sperm and egg cells that are required for sexual reproduction. This process is very difficult to study in humans and so we use a model organism, the budding yeast. When deprived of nutrients yeast cells stop dividing and initiate a process similar to human sperm formation, however instead to sperm, spores are formed. To accomplish this process the cells must "turn off" many of the genes required for growth and cell division while they "turn on" entirely new sets of genes that encode proteins required for the transformation from proliferating cells into spores. We have discovered that the proteins controlling expression of meiosis-specific genes become modified by the addition of phosphate during the process of meiosis and spore formation and these modifications have a huge impact on their function. Proteins that repress the meiosis-specific genes become inactivated and a protein that induces the meiosis-specific genes becomes activated by this modification process. We have identified a meiosis-specific protein kinase (Ime2) that we suspect is responsible for phosphorylating the transcription factors that control the meiosis-specific genes. We are using a series of genetic biochemical methods to determine how phosphorylation influences the properties of the transcriptional activators and repressors that control the meiosis-specific genes. This research is aimed at understanding how one set of meiosis-specific genes is regulated. In particular we are focusing on how these genes are repressed during growth and what changes happen to the repressor to allow the activation of these genes during meiosis and sporulation. Through our investigations of yeast we have identified several proteins that perform essential functions for the spore formation process; several of these are very similar to human proteins that are required for gamete formation. This research program will increase our understanding of the basic biochemistry that regulates gene expression and will provide insight into the control of gamete formation that is requuired for sexual reproduction.