Sexual Development of the Drosophila Germline

描述（由申请人提供）：生殖系性别认同的建立对于生殖系干细胞的性别特异性发育和精子与卵子的产生至关重要。因此，它是动物有性繁殖和人类生育的一个重要方面。生殖细胞依靠来自体细胞性腺的信号来确定其性别，但在苍蝇、老鼠和人类等生物中，生殖细胞的性染色体基因型对种系性发育也很重要。最终，种系性别认同必然导致生殖细胞中基因表达的性别特异性程序。体细胞信号和生殖细胞自主因子如何结合起来调节生殖系性别特异性基因表达是生殖系性别决定的一个核心问题，但在任何生物体中都知之甚少。在果蝇中，来自雄性和雌性体细胞的外在信号调节着生殖系的性别认同。我们已经表明，男性信号通过JAK/STAT途径起作用，但女性信号的性质仍然未知。本质上，生殖系性染色体基因型激活了雌性生殖系性别决定基因性致死（sex lethal, Sxl）的表达。Sxl如何在雌性生殖系中被激活，以及Sxl如何调节雌性生殖细胞的身份也是未知的。最后，这些外在和内在的机制必须最终导致基因表达的性别特异性模式。我们发现植物同源结构域手指蛋白7 （PHF7）是调节男性种系身份的关键因素，通过识别特定修饰形式的组蛋白H3，作为表观遗传信息的“读者”。然而，我们还不知道PHF7如何调节雄性种系基因表达。在本研究中，我们将采用一种综合的方法来研究来自体细胞的外在信号如何与种系内在信号结合，启动种系性别决定，并产生一种性别特异性的种系基因表达模式。这项工作将为性别认同是如何建立并用于影响生殖系发育的重要方面（如生殖系干细胞的性别特异性形成）提供一个全面的模型。该模型可作为果蝇和其他动物物种（包括人类）生殖系性别决定的后续研究框架。

DESCRIPTION (provided by applicant): The establishment of sexual identity in the germline is critical for the sex-specific development of germline stem cells and the production of sperm vs. eggs. Thus, it is an essential aspect of animal sexual reproduction and human fertility. Germ cells depend on signals from the somatic gonad to determine their sex, but in organisms such as flies, mice and man, the sex chromosome genotype of the germ cells is also important for germline sexual development. Ultimately, germline sexual identity must result in a sex-specific program of gene expression in the germ cells. How somatic signals and germ cell autonomous factors combine to regulate sex-specific gene expression in the germline is a central question for germline sex determination about which little is known in any organism. In Drosophila, extrinsic signals from both the male soma and the female soma regulate germline sexual identity. We have shown that the male signal acts through the JAK/STAT pathway, but the nature of the female signal remains unknown. Intrinsically, the germline sex chromosome genotype activates expression of the germline sex determination gene Sex lethal (Sxl) in females. How Sxl becomes activated in the female germline, and how Sxl regulates female germ cell identity are also unknown. Lastly, these extrinsic and intrinsic mechanisms must ultimately give rise to a sex-specific pattern of gene expression. We have identified Plant homeodomain finger protein 7 (PHF7) as a critical factor in regulating male germline identity that acts as a "reader" of epigenetic information by recognizing specific modified forms of histone H3. However, we do not yet know how PHF7 functions to regulate male germline gene expression. In this proposal, we will take an integrated approach to investigate how extrinsic signals from the soma combine with germline intrinsic cues to initiate germline sex determination and generate a sex-specific pattern of germline gene expression. This work will provide a comprehensive model for how sexual identity is established and used to influence important aspects of germline development, such as the sex-specific formation of germline stem cells. This model can be used as a framework for continued studies of germline sex determination in Drosophila and other animal species, including humans.