Special Reviews

Germ Versus Soma Decisions: Lessons from Flies and Worms

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Science  20 Apr 2007:
Vol. 316, Issue 5823, pp. 392-393
DOI: 10.1126/science.1140846

Abstract

The early embryo is formed by the fusion of two germ cells that must generate not only all of the nonreproductive somatic cell types of its body but also the germ cells for the next generation. Therefore, embryo cells face a crucial decision: whether to develop as germ or soma. How is this fundamental decision made and germ cell fate maintained during development? Studies in the nematode worm Caenorhabditis elegans and fruit fly Drosophila identify some of the decision-making strategies, including segregation of a specialized germ plasm and global transcriptional regulation.

The C. elegans embryo separates the germ lineage from somatic lineages progressively, through a series of four asymmetric divisions (1). During each of those divisions, a specialized cytoplasm, or “germ plasm,” is partitioned to one daughter cell, the P cell (Fig. 1). After the separation of the germ and soma is complete, the P4 cell serves as the sole primordial germ cell (PGC). The germline fate of P4 probably relies on both inheritance of germ plasm components and segregation of somatic differentiation factors away from the germ lineage. In Drosophila, the location of germ cells in the embryo is already established during oogenesis, when maternally synthesized germ plasm components assemble at only one pole of the oocyte (Fig. 1). During the initial stages of embryogenesis, the fly embryo divides by nuclear rather than cellular divisions. Those nuclei that enter the posterior germ plasm become PGCs (2).

Fig. 1.

Formation of PGCs and landmark stages in their development in C. elegans and Drosophila. Germ plasm is represented by red granules. Key regulators mentioned in the text are noted in yellow boxes. Blue arrow in final panel indicates direction of germ cell migration in Drosophila.

Despite their different formation strategies, both worms and flies rely on the passage of specialized germ plasm from the oocyte to the future germ cells. Induction, an alternative mode of germ cell specification, operates in other organisms, including mice (3).

Newly Formed Germ Cells Are in a Transcriptionally Repressed State

A common feature of early germ cells in worms and flies is their transcriptional quiescence (Figs. 1 and 2). One likely role is to protect early germ cells from expressing somatic differentiation genes. Transcriptional quiescence is achieved through a repression program that regulates the core transcriptional machinery as well as chromatin states.

Fig. 2.

Germ cell traits. (A to F) Posterior end of wild-type [(A) to (C)] and pgc mutant [(D) to (F)] Drosophila blastoderm embryos. The PGCs (arrows) contain the polar plasm component Vasa [green in (A) and (D)]. The somatic nuclei contain elongating RNA Pol II [red in (A), (B), (D), and (E)] and H3K4me [green in (B) and (E)] and produce tailless mRNA [blue in (C) and (F)]. In wild-type embryos [(A) to (C)], PGCs (white arrows) lack elongating RNA Pol II, H3K4me, and tailless mRNA. In pgc mutant embryos [(D) to (F)], PGCs (white arrows) contain those three markers. Overlap of green and red in (B) and (E) appears yellow. Images adapted from (7) with permission from Elsevier. (G) Electron micrograph of a P granule (electron-dense mass labeled Pg, containing internal electron-dense material marked by an open arrow) overlying five nuclear pores (black arrows) in the adult C. elegans germ line. Reprinted from (17) with permission from Elsevier. (H) Wild-type L1 C. elegans larva. P granules are restricted to the two PGCs Z2 and Z3 (arrows). (I) mep-1 mutant L1 larva. P-granule markers (e.g., PGL-1) are ectopically expressed in somatic cells.

The earliest phase of repression is mediated at the level of transcription elongation in both organisms, as the germ line and soma are being separated from each other (4). Proteins involved in preventing RNA polymerase II (Pol II) elongation in germ cells have been identified in both organisms. The zinc finger protein PIE-1 is a key regulator in worms (5). In embryos that lack PIE-1 activity, newly formed germ cells contain elongating Pol II and produce mature mRNAs (1, 4, 5). In these mutants, the development of germ cells is similar to that of their somatic sister cells, and the embryos die. Mechanistically, PIE-1 apparently competes with the tail of Pol II for the enzymes that modify Pol II for elongation (6). In flies, the peptide Pgc and the translational repressors Nanos and Pumilio control transcriptional silencing (4, 79). As in pie-1 mutants, germ cells that lack either Pgc or Nanos activity show elongating Pol II activity and express genes characteristic of somatic cells (7, 8, 10) (Fig. 2, A, C, D, and F). These “transformed” cells either undergo apoptosis, a somatic cell death pathway, or adopt somatic cell fates (10). The mechanism (or mechanisms) by which Pgc and the Nanos and Pumilio translational repressors prevent elongation and the relationship between these regulators are unclear.

A chromatin-based phase of transcriptional repression kicks in soon after P4 divides to generate the Z2 and Z3 cells, at the ∼100-cell stage of worm embryogenesis, when PIE-1 disappears and PIE-1–mediated transcriptional repression ends (11). One indicator of this transition is the disappearance from Z2 and Z3 of histone modifications that are associated with transcriptional competence, such as methylation of lysine-4 of histone H3 (H3K4me). One key regulator of the transition is Nanos; H3K4me status is perturbed in Z2 and Z3 depleted of the two Nanos homologs NOS-1 and NOS-2 (11). In flies, H3K4me is absent from embryonic germ cells from the time they are born. This absence requires Pgc and Nanos (7, 11) (Fig. 2, B and E). Transcriptional activity and H3K4me appear as germ cells initiate their migration and Pgc disappears (11).

Breakdown of the Germ Versus Soma Distinction

Both transcriptional quiescence and translational control protect germ cells from expressing somatic differentiation genes. Germ-to-soma transformations, which resemble teratomas in mammals, highlight the need for insulation of germline cells from conditions or signals that send them down a somatic differentiation pathway. In the adult worm, germ lines lacking the translational regulators GLD-1 and MEX-3 lose their germ granules and express markers characteristic of neurons and muscles (12). Conversely, somatic cells may require protection from conditions or signals that send them down a germline differentiation pathway. Loss of some of the C. elegans synMuv B chromatin regulators, such as LIN-35/Retinoblastoma and members of the nucleosome remodeling and histone deacetylase (NuRD) complex (e.g., MEP-1), causes somatic cells to display germline traits, such as germ granules and enhanced RNA interference (13, 14) (Fig. 2, H and I). This ectopic expression of germline traits by somatic cells depends on the histone H3K36 methyltransferase MES-4 and the chromodomain protein MRG-1 (1315). These chromatin regulators are known to be critical for germline development, but the mechanistic details in the soma are unclear.

Roles of Germ Granules

A distinctive feature of germ cells is possession of specialized germ plasm, which contains unique cytoplasmic organelles generically referred to as germ granules and specifically called polar granules in flies and P granules in worms (Fig. 2, G and H). Polar granules and P granules share some components, such as the RNA helicase Vasa in flies and the related germline helicases (GLHs) in worms, and they contain numerous species-specific proteins, such as Oskar in flies and PGL-1 in worms (1, 2, 4). Although the precise roles of these granules are still being worked out, it is clear that they are intimately associated with germline fate in all organisms, including those organisms that specify germ cells by inductive signals (3).

What roles do germ granules play? Studies in flies and worms suggest that a primary role is in handling RNA. Germ granules are rich in RNA and predicted RNA-binding proteins, and many RNAs and proteins are either specifically localized to or protected from degradation in these granules (16). The location of germ granules over nuclear pores positions them to encounter mRNAs during their transport from the nucleus and may contribute to control of mRNA translation and localization within the cytoplasm (17, 18) (Fig. 2G). Functionally, germ granules may be related to P bodies. The latter have been shown in yeast and mammalian cells to participate in mRNA decay, RNA interference, and translation inhibition by microRNAs. Many P-body proteins are found in germ granules in worms and flies (1922). Germ cells appear to be particularly dependent on RNA-based regulation and may benefit from consolidating RNA-processing machinery into large granular assemblies. Throughout the life cycle, however, germ granules are dynamic in morphology, composition, and RNA regulatory function. P body–like activities may thus be only one aspect that regulates germline fate.

Summary and Outlook

Flies and worms share several strategies to establish and maintain germ cells and protect them from somatic fates. Both systems segregate specialized germ plasm to the PGCs. The RNA-rich granules in germ plasm serve roles in localization, protection, and translation of mRNAs. Although mammalian germ cells are not specified by segregated germ plasm, they do contain germ plasm components. Transcriptional repression in early PGCs is a common theme to prevent PGCs from differentiating in the same way as their somatic neighbors, although the regulators—worm PIE-1, fly Pgc, and mammalian Blimp1—differ between species (3). Studies across species promise to provide more mechanistic insights into how germ plasm and transcriptional regulation specify germ cells in the early embryo and protect germ cell fate throughout life.

References and Notes

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