The mechanism of hmgcr-dependent germ cell migration

在许多物种中，原始生殖细胞（PGCs）是从体细胞性腺分离出来的。在早期胚胎发育过程中，PGCs通过体细胞组织迁移到目标性腺原基。PGCs的定向迁移是一个主动的过程，被认为是由吸引和排斥信号介导的。3-羟基-3-甲基戊二酰辅酶还原酶（HMGCR）是一种通用的代谢酶，是吸引迁移生殖细胞的必要和充分的酶。HMGCR如何介导生殖细胞沿高度特征性路径的引导尚不清楚。提出的工作的目标是表征HMGCR在指导果蝇PGC迁移中使用药理学和遗传学方法的作用。药理学试剂，包括表征良好的HMGCR下游通路分支的抑制剂，提供了一种直接的方法来确定高分支通路的哪个分支介导PGC引导。为了确定hmgcr下游的基因位点，还将对主要增强hmgcr弱突变的轻度迁移缺陷的突变进行遗传筛选。这些实验将有助于确定HMGCR途径产生的生殖细胞引导信号的分子性质以及生殖细胞如何接收该信号。

In a number of species the primordial germ cells (PGCs) originate separate from the somatic gonad. During early embryonic development, the PGCs migrate through somatic tissues to their target, the gonadal primordia. The directed migration of PGCs is an active process, thought to be mediated by both attractive and repulsive signals. 3-hydroxy-3- methylglutaryl coenzymeA reductase (HMGCR), a general metabolic enzyme, is both necessary and sufficient to attract migrating germ cells. How HMGCR mediates the guidance of germ cells along a highly characteristic path is not known. The goal of the proposed work is to characterize the role of HMGCR in directing Drosophila PGC migration using both pharmacological and genetic approaches. Pharmacological reagents, including inhibitors of well characterized pathway branches downstream of HMGCR, provide a directed means of identifying which branch of the highly branched pathway is mediating PGC guidance. To identify genetic loci that act downstream of hmgcr, a genetic screen for mutations that dominantly enhance the mild migratory defects of a weak mutation in hmgcr will also be carried out. These experiments will aid in identifying the molecular nature of a germ cell guidance signal produced by the HMGCR pathway and how germ cells receive this signal.