Embryonic Development of the Mammalian Epididymis

哺乳动物附睾的胚胎发育

• 批准号: 8442925
• 负责人: Barry T. Hinton
• 金额: $ 29.96万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8442925
• 关键词: Actins; Apical; Apoptosis; Area; Cell Polarity; Cell Proliferation; Cell Shape; Cell division; Cells; Cochlea; Congenital Abnormality; Cytoskeleton; DNA Sequence Rearrangement; Defect; Development; Duct (organ) structure; Ductal; Embryo; Embryonic Development; Epididymis; Event; Failure; Fertility; Fetal Development; Gene-Modified; Goals; Growth; Imaging Techniques; Individual; Lead; Liquid substance; Male Infertility; Molecular; Morphogenesis; Mus; Nature; Neural Tube Development; Neural tube; Organ; Organ Culture Techniques; Outcome; Outcome Study; Pathway interactions; Play; Polycystic Kidney Diseases; Positioning Attribute; Process; Regulation; Reproductive Biology; Role; Sperm Maturation; Structure of mesonephric duct; Testing; Time; Tube; cell motility; gastrulation; innovation; intercalation; interest; kidney cell; male; member; nephrogenesis; novel; public health relevance; rho

DESCRIPTION (provided by applicant): The epididymis is critical to the process of sperm maturation because it provides a unique luminal fluid microenvironment that allows for sperm maturation and survival, and disruptions to this function lead to male infertility. However, disruptions to epididymal function may also arise as a consequence of abnormal fetal development, although very little is known either of the process of epididymal development or of the nature and causes of congenital defects that lead to male infertility. A major event during Wolffian/ epididymal duct embryonic development is elongation and coiling, presumably as a result of cell proliferation. However, in this application we hypothesize that an additional mechanism, cell intercalation contributes to elongation and coiling. Elongation and coiling is not a trivial event but must be highly coordinated with its specialized function of providing a unique luminal fluid microenvironment that is so important for sperm maturation. We have chosen the embryonic time period because cell proliferation and ductal coiling are initiated and it is a time when potential defects can occur. Examining the mechanism(s) of cell intercalation as a means to elongate and coil the Wolffian duct is novel, and we are especially interested in examining the contribution of a member of the planar cell polarity pathway (PCP), Ptk7, as a regulator of this important event during Wolffian duct morphogenesis. A combination of genetically modified mice, modern imaging techniques, in vitro organ culture techniques, and gene modifying approaches will be used to test the hypotheses outlined in the following three specific aims: (1) To test the hypothesis that Ptk7 plays an important role in cell shape and cell positioning, which in turn allow the Wolffian duct to undergo the morphogenic events of elongation and coiling. (2) To test the hypothesis that Ptk7 regulates specific cell rearrangements by modulating the basolateral protrusive activity and the orientation of cell division yet maintaining cell proliferaion during Wolffian duct embryonic development. (3) To test the hypothesis that cell intercalation during Wolffian duct elongation and coiling is driven by polarized changes in cytoskeleton organization, and is regulated by Ptk7 through activation of the Wnt/PCP pathway. In summary, the hypothesis that the Wolffian duct can elongate via cell intercalation is highly novel and innovative because it has always been assumed that elongation of the epididymal duct is via cell proliferation only. In addition, we have uncovered an unusual regulatory molecule, Ptk7, which is hypothesized to play a role in Wolffian duct elongation and coiling. The anticipated outcomes of this study will not only have a major impact on an area of reproductive biology that has been poorly understood, but will also contribute to our understanding of the fundamental process of tube morphogenesis. Specifically they will provide an understanding as to how the regulation of growth of the epididymis during development is important clinically.

描述（由申请人提供）：附子症对于精子成熟过程至关重要，因为它提供了独特的腔液流体微环境，该环境允许精子成熟和生存，并且对这种功能的破坏导致男性不孕症。然而，由于异常的发育，对附睾功能的破坏也可能引起，尽管在附睾发育的过程中鲜为人知，或者是先天性缺陷的性质和原因，导致男性不育。沃尔夫语/附子导管胚胎发育期间的一个主要事件是伸长和盘绕，大概是由于细胞增殖而导致的。但是，在此应用中，我们假设一种附加的机制，细胞插入有助于伸长和盘绕。伸长和盘绕并不是一个琐碎的事件，而必须与其专门功能高度协调，以提供独特的腔内流体微环境，这对于精子成熟至关重要。我们之所以选择胚胎时间段，是因为启动了细胞增殖和导管盘，这是可能发生潜在缺陷的时候。研究细胞插入的机制作为拉长和线圈的一种手段，沃尔夫管道是新颖的，我们特别有兴趣研究沃尔夫·波利夫（Wolffian）管道形态发生期间这种重要事件的调节器PTK7，PTK7，PTK7，PTK7，PTK7的贡献。将使用转基因修饰的小鼠，现代成像技术，体外器官培养技术和基因修饰方法的组合来测试以下三个特定目的中概述的假设：（1）测试PTK7在细胞形状和细胞定位中扮演重要作用的假说，这会允许wolffian duct and nock and ofer nock and ofer nock and cogent and ofer nock and the nock and oferge andong andong andong。 （2）测试PTK7通过调节基底外侧突出活性和细胞分裂的方向而在沃尔夫·沃克斯胚胎发育过程中维持细胞增殖的假设。 （3）测试以下假设：沃尔夫管道延伸和盘绕过程中的细胞插入是由细胞骨架组织的极化变化驱动的，并且受PTK7的调节，并通过激活WNT/PCP途径来调节。总而言之，沃尔夫语导管可以通过细胞插入伸长的假设是高度新颖和创新的，因为一直假定附子导管的伸长仅通过细胞增殖。此外，我们发现了一个异常的调节分子PTK7，该分子在沃尔夫管道延伸和盘绕中发挥了作用。这项研究的预期结果不仅会对鲜为人知的生殖生物学领域产生重大影响，而且还将有助于我们对管子形态发生的基本过程的理解。具体而言，他们将提供有关在发育过程中附睾增长的调节如何在临床上很重要的理解。