Mechanisms regulating the timing of developmental events in the early mouse embryo

点击翻译按钮获取中文摘要

An unanswered fundamental question in biology is what ensures that individuals of a particular species are all roughly the same size at birth. This highly reproducible rate of embryonic development is also clinically relevant as it is essential for the health of the foetus: retarded growth is an important cause of foetal and neonatal morbidity and mortality; over-growth is an important contributor to congenital malformations. In spite of the importance of understanding how embryo growth is regulated, we still know very little about this process. In this proposal we aim to tackle this problem. We will perform our studies using the mouse embryo as our model system as these embryos are amenable to manipulations that would not be ethical in humans. We will focus on analysing the period just after the embryo has implanted into the uterus, as during this period it has been shown that undersized embryos display catch-up growth and oversized embryos reduce in size until they are the same size as normal embryos. By analysing how undersized and oversized embryos scale to the size of normal ones we anticipate that we will gain understanding on the processes that ensure that all embryo grow at a similar rate. Specifically, we will do three things:1) We will establish how undersized and oversized embryos adjust their growth rate by studying if it is by modulating the rate at which their cells divide and/or the rate at which their cells die.2) We will determine what signals are exchanged between cells to promote the growth of undersized embryos and restrict the growth of oversized embryos. For this we will exploit our preliminary observations that indicate that a pathway that regulates growth by integrating nutrient or growth factors is important. To test the importance of this pathway we will manipulate how the cells of the embryo respond to these inputs to establish which of them drives the catch-up growth of undersized embryos and the slowing down in growth of oversized ones. We will also study how these inputs they act differently in embryos that are not the right size.3) During the period that oversized and undersized embryos adjust their size they start to form all the different types of cells that will form the different organs. For this reason we will study how the mechanisms that ensure the embryos are the proper size affect the formation of the different cell types of the embryo.Given the importance of embryo size for a normal pregnancy, we expect that the above described studies will help us develop methods to identify and treat embryos with abnormal growth rates early on in pregnancy.