Mechanisms of pituitary gonadotrope cell maintenance and renewal in adult mice

点击翻译按钮获取中文摘要

The organs of the body, like the brain and heart, are made up of specialized cell types that perform the necessary functions of those organs. Most cells in most organs die and are replaced continuously throughout life. These include sperm cells in the testicles and the cells that line the intestines. Other cells, such as neurons in the brain or so-called cardiomyocytes of the heart, are thought to last the lifetime of the individual and are not replaced, even when damaged or dying. That is why, for example, events such as strokes and heart attacks are thought to produce irreversible effects on the brain and heart, whereas other organs (such as bones and muscles) can repair themselves following injury. Most organs of the body possess the ability to replace themselves throughout life, though do so at different rates and in different ways. For example, some organs have what are most commonly called progenitor or committed stem cells that have the ability to repopulate a given organ with the cell types that comprise them but that lack the ability to repopulate cell types in other organs. In other organs, some cell types have the ability to self-renew. That is, they divide, making copies of themselves. There are still other ways for cells to be replaced. For example, some tissues are comprised of several different cell types with different functions. Under some conditions, one cell type may transform into another cell type. Therefore, the body has evolved many different mechanisms for replacing cells in different organs. Collectively, this process is referred to as tissue homeostasis and simply reflects the fact that cells get damaged and die over the lifetime of the individual and need to be replaced for the individual to continue to survive in a relatively healthy state. Arguably, aging reflects the reduced ability of the body to replace cells as individuals age. The pituitary gland is an organ that sits at the base of the brain. It is comprised of five main cell types, each of which makes different hormones that control different aspects of ovarian, testicular, adrenal, thyroid, liver, and breast function. Hormones are chemical messengers made in one organ or tissue that travel through the bloodstream to regulate the activity of other organs or tissues. In the case of the reproductive system, a cell type in the pituitary gland called the gonadotrope makes two hormones called follicle-stimulating hormone and luteinizing hormone. Once released into the blood from the gonadotrope cell, these two hormones travel to the ovaries and testicles where they control the development of the gametes (eggs and sperm) as well as the production of steroid hormones such as testosterone and estrogen. Though humans and other mammals have the capacity to reproduce for much of their adult lives, we do not yet know whether the gonadotrope cells of the pituitary are born early in fetal development and last the lifetime of the individual (as with brain and heart cells) or whether they die and are replaced throughout life. If they are replaced, we do not know how the body accomplishes this feat. In the present grant application, we propose to use genetically modified mice to answer these previously unanswered questions. The results of this work will advance our understanding of one the most fundamental aspects of vertebrate reproductive physiology.