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

描述(申请人提供)：在果蝇中，成年生殖系的祖细胞，原始生殖细胞(PGCs)，形成于细胞前胚层胚胎的后极。PGCS的规范和发展过程与周围SOMA的过程有很大不同。这些差异包括早熟细胞化、胚胎外表面的隔离、有限的有丝分裂潜力、转录静止和特殊的染色质结构。与胞体不同的是，PGC特性的指定和随后的阐述被认为完全依赖于细胞自主因子，这些因子在卵子发生过程中组装成一个特殊的细胞质，即极质。除了协调PGC的发育外，这些母性因素被认为可以使新形成的PGC免受细胞-细胞信号通路的不利影响，这些信号通路被用来形成邻近的胞体。然而，我们对BMP信号通路的初步实验挑战了长期以来对PGC规范的看法。我们发现，PGCs不仅能够响应来自体细胞的BMP信号，而且这些信号影响着PGCs的规范和发育。在本申请概述的研究中，我们建议重新检查PGC规范的问题，重点关注这一非自主信号通路在PGC发展中的作用。我们将研究几个问题，这些问题对于我们理解PGC的命运是如何决定的，以及PGC随后如何发展为生殖系干细胞(GSC)是至关重要的。我们将确定BMP信号通路在早期胚胎中形成的PGCs和中期胚胎发育过程中融合到胚胎性腺中的PGCs中所起的作用。在胚胎发育中期，我们的研究将集中在这一途径如何影响PGCs向GCSs的转化。我们还将分析BMP途径在PGCs/GSCs女性化过程中一个意想不到的新角色。在早期胚胎中，我们的研究将集中在PGC特性的指定和维持的机制上。我们将研究BMP途径如何与细胞自主的母性因子相交，以建立和阐述PGC的命运。我们还将确定BMP途径是否在编程PGC特定的基因活性模式中发挥重要作用。

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.