Unexpected roles for BMP signaling in the specification of the embryonic germline

BMP 信号在胚胎种系规范中的意外作用

• 批准号: 8837033
• 负责人: Paul D Schedl
• 金额: $ 30.34万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-11 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8837033
• 关键词: Address; Adult; Adverse effects; Animal Model; Animals; Architecture; Blastoderm; Cell Cycle; Cells; Characteristics; Chromatin; Cues; Cytoplasm; Deposition; Development; Drosophila genus; Drosophila melanogaster; Embryo; Embryonic Development; Female; Feminization; Generations; Genes; Germ Cells; Gonadal structure; Health; Maintenance; Messenger RNA; Mitotic; Oocytes; Oogenesis; Organism; Pathway interactions; Pattern; Play; Process; Proteins; RNA Interference; Research; Role; Signal Pathway; Signal Transduction; Somatic Cell; Specific qualifier value; Staging; Stem cells; Structure of primordial sex cell; Surface; Tissues; Transplantation; base; cell type; germline stem cells; intercellular communication; neuronal cell body; novel; progenitor; programs; research study; stem cell fate; transcription factor; translation factor

DESCRIPTION (provided by applicant): In Drosophila melanogaster the progenitors of the adult germline, the primordial germ cells (PGCs), are formed at the posterior pole of the pre-cellular blastoderm embryo. The process of PGCs specification and development differs substantially from that of the surrounding soma. Amongst the differences are precocious cellularization, sequestration on the outside surface of the embryo, limited mitotic potential, transcriptional quiescence and a special chromatin architecture. Also unlike the soma, the specification and subsequent elaboration of PGC identity is thought to depend exclusively on cell autonomous factors that are assembled into a specialized cytoplasm, the pole plasm, at the posterior of the oocyte during oogenesis. In addition to orchestrating PGC development, these maternal factors are thought to insulate newly formed PGCs from the adverse effects of the cell-cell signaling pathways that are deployed to pattern the neighboring soma. However, our preliminary experiments on the BMP signaling pathway challenge this long held view of PGC specification. We find that PGCs are not only capable of responding to BMP signals from the soma, but also that these signals impact the specification and development of the PGCs. In the studies outlined in this application we propose to re-examine the problem of PGC specification, focusing on the role of this non-autonomous signaling pathway in PGC development. We will investigate several issues that are central to our understanding of the mechanisms underlying how PGC fate is determined and how the PGCs subsequently development into germline stem cells (GSCs). We will determine what role the BMP signaling pathway plays in the developing PGCs in the period between the formation of these cells in the early embryo and their coalescence into the embryonic gonad during mid-embryogenesis. In mid-embryogenesis, our studies will focus on how this pathway impacts the transformation of PGCs into GCSs. We will also analyze an unexpected and novel role of the BMP pathway in the feminization of the PGCs/GSCs. In the early embryo, our studies will focus on the mechanisms involved in the specification and maintenance of PGC identity. We will investigate how the BMP pathway intersects with the cell autonomous maternal factors to establish and elaborate PGC fate. We will also determine whether the BMP pathway plays an instrumental role in programming PGC specific patterns of gene activity.

描述（由申请人提供）：在果蝇中，成年种系的祖细胞（原始生殖细胞（PGC））在细胞前胚胚胚胎的后极形成。 PGC规范和发育的过程与周围的SOMA的过程有很大不同。差异包括早熟的细胞化，胚胎外表面上的隔离，有限的有丝分裂潜力，转录静止和特殊的染色质结构。同样与SOMA不同，PGC身份的规范和后续阐述被认为仅取决于在卵子发生过程中卵母细胞后部组装成专门的细胞质（POL）的细胞自主因素。除了策划PGC的发展外，这些母体因素还被认为使新形成的PGC与细胞细胞信号通路的不良反应隔离，这些途径被部署以模拟相邻的SOMA。但是，我们对BMP信号通路的初步实验挑战了PGC规范的长期观点。我们发现，PGC不仅能够响应SOMA的BMP信号，而且这些信号会影响PGC的规范和开发。在本应用程序中概述的研究中，我们建议重新检查PGC规范的问题，重点关注这种非自主信号通路在PGC开发中的作用。我们将研究几个问题，这些问题是我们对PGC命运如何确定基础机制以及PGC随后如何发展为种系干细胞（GSC）的核心。我们将确定在早期胚胎中这些细胞在这些细胞形成的时期中，BMP信号通路在发育中的PGC中的作用与它们在中期生成期间与胚胎性腺的合并之间的作用。在中期生成中，我们的研究将集中于该途径如何影响PGC向GCSS的转化。我们还将分析BMP途径在PGC/GSC女性化中的意外和新作用。在早期的胚胎中，我们的研究将重点关注PGC身份规范和维持的机制。我们将研究BMP途径如何与细胞自主母体因素相交以建立和详细的PGC命运。我们还将确定BMP途径是否在编程PGC特定基因活性模式中起具有工具作用。