SGER: Development of a Mouse With Inducible Estrogen Receptor Alpha Function

雌激素是一种类固醇激素，在一生中都很重要。它参与细胞迁移、骨骼发育、生殖发育、神经发生、心脏功能甚至神经可塑性和认知等功能，以及它作为生殖激素的众所周知的作用。雌激素在细胞水平上通过两种已知的主要分子受体，α (ER-a)和β (ER-B)起作用。这些受体是促进细胞生长和增殖的转录因子。通过对基因敲除（KO）小鼠的研究发现，ER-a受体是参与生殖社会行为、探索行为、学习记忆等非生殖行为的主要受体，在发育过程中也具有重要作用。这个SGER项目使用一种新颖的方法来创建一个“可诱导的”遗传KO小鼠品系，而不是目前可用的简单敲除。诱导型基因敲除的概念并不新鲜，但目前还没有针对任何类固醇受体的可逆基因敲除，这些受体在大脑中分布如此广泛且具有重要的功能。ER-a的诱导基因表达将允许这种类固醇受体功能被可逆地操纵，因此在不同的发育阶段和成人中，不仅可以关闭基因表达，还可以再次打开基因表达，从而可以探索这种重要受体的功能在生命中是否存在不同的“关键时期”。这是一个高影响/高风险项目，因为结果不明确，但成功的潜在影响是广泛的。如果成功，这一结果将导致对类固醇激素的时间依赖性功能的进一步研究，并将在神经内分泌学以外的领域产生重大影响，如发育生物学和认知神经科学。该项目也为衔接分子生物学和神经内分泌学的研究生提供了宝贵的培训经验。

Estrogen is a steroid hormone that is important throughout the lifespan. It is involved in functions including cell migration, bone development, reproductive development, neurogenesis, heart function and even neural plasticity and cognition, as well as its well-known actions as a reproductive hormone. Estrogen acts at the cellular level through two main known molecular receptors, alpha (ER-a) and beta (ER-B). These receptors are transcription factors that promote cell growth and proliferation. The ER-a receptor is known from studies on genetic knockout (KO) mice to be the major receptor involved in reproductive social behaviors, and in non-reproductive behaviors such as exploratory behavior, learning and memory, as well has having an important function in development. This SGER project uses a novel approach to create an 'inducible' genetic KO mouse strain, rather than the simple knockouts currently available. The concept of an inducible knockout is not new, but there has been no reversible knockout developed for any of the steroid receptors, which have such widespread distribution and functional importance in the brain. The inducible genetic expression of ER-a will allow this steroid receptor function to be manipulated reversibly, and so turn the gene expression not only off, but also on again, during different stages of development and in adults, allowing exploration of whether there are distinct 'critical periods' in life for the function of this important receptor. This is a high-impact/high-risk project because the outcome is not clear, but the potential impact of success is wide-ranging. If successful, the results will lead to further studies on time-dependent functions of steroid hormones, and will have a high impact extending beyond neuroendocrinology into the areas such as developmental biology and cognitive neuroscience. The project also provides a valuable training experience for a graduate student bridging molecular biology with neuroendocrinology.