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Genetics of germ cell development

Key Points

  • Germ cells are specialized cells that are responsible for transmitting the genome of an individual organism to its offspring.

  • The defining characteristic of the germ cells is their ability to undergo meiosis, in which the diploid genome is reduced to a haploid genome that can combine with another haploid genome at fertilization.

  • Many of the factors specifying germ cell identity are RNA-binding factors, and many of these RNA-binding factors are conserved in the germ cells across multiple species.

  • Maintenance of a transcriptionally repressed state is a characteristic of early germ cells in multiple species. Repression is accomplished both by the direct inhibition of RNA polymerase II and by the establishment of a repressive chromatin configuration.

  • The decision to stop mitotic proliferation and to enter meiosis is timed differently in the different species and in different sexes of the same species. In some cases, a proliferative pool of germline precursors is retained after this decision, and in some cases all available germ cells enter meiosis together.

  • The later steps of germ cell development set up the cues that will guide the earliest stages of embryogenesis.

  • Germ cells represent the closest in vivo equivalent to in vitro pluripotent stem cell systems; understanding germ cell biology will provide new insights into the nature of pluripotency.

Abstract

The germ line represents a continuous cellular link between generations and between species, but the germ cells themselves develop in a specialized, organism-specific context. The model organisms Caenorhabditis elegans, Drosophila melanogaster and the mouse display striking similarities, as well as major differences, in the means by which they control germ cell development. Recent developments in genetic technologies allow a more detailed comparison of the germ cells of these three organisms than has previously been possible, shedding light not only on universal aspects of germline regulation, but also on the control of the pluripotent state in vivo and on the earliest steps of embryogenesis. Here, we highlight themes from the comparison of these three alternative strategies for navigating the fundamental cycle of sexual reproduction.

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Figure 1: Summary of germ cell development in C. elegans, D. melanogaster and the mouse
Figure 2: Mechanism of transcriptional repression by PIE-1 and PGC.
Figure 3: Genetic pathways controlling germ cell sex-determination and meiotic entry.
Figure 4: Meiotic arrest in developing oocytes.

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Acknowledgements

The authors would like to acknowledge D. de Rooij for useful discussions during preparation of this review, and R. Desgraz, T. Endo, A. Godfrey, J. Hughes, M. Kojima, J. Mueller and K. Romer for comments on the manuscript.

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Confocal microscopy movies associated with reference 33, showing the migration of living, fluorescently labelled primordial germ cells in the mouse embryo

Glossary

Gametes

Haploid, differentiated germ cells: mature sperm and eggs.

Zygotic

Referring to a zygote, which is a one-celled embryo as the initial product of fertilization.

Germ plasm

Specialized cytoplasm that contains factors that are necessary and sufficient for germ cell specification. Germ plasm may or may not have a known physical correlate in a given species.

P granules

Cytoplasmic structures comprising the germ plasm in Caenorhabditis elegans.

Oocytes

Female germ cells that have initiated meiosis. Because meiosis is not complete in the oocyte until fertilization, mature female gametes are oocytes.

Polar granules

Cytoplasmic structures comprising the germ plasm in Drosophila melanogaster.

Epiblast

A cup-shaped sheet of cells derived from the inner cell mass that will eventually form all tissues of the embryo proper.

Extra-embryonic ectoderm

Ectodermal tissue that is derived from the epiblast but does not contribute to the embryo proper. Ectoderm is one of the three primary germ layers produced during early embryonic development.

Anterior visceral endoderm

(AVE). Cell layer underlying the epiblast in the mouse embryo. It does not contribute to the embryo proper but serves important signalling functions during embryogenesis.

Primordial germ cells

A term used for cells early in the germ cell lineage, before they have initiated meiosis or begun sex-specific differentiation.

Gastrulation

The process by which the three primitive germ layers are formed in the early embryo; it is one of the first major differentiation events in development.

Pre-initiation complex

A protein complex made up of general transcription factors that positions RNA polymerase II (RNAPII) at gene transcription start sites and positions DNA in the RNAPII active site.

Polycomb

A chromatin regulatory complex that represses gene expression; it is associated with deposition of the histone mark H3K27me3.

Germline stem cells

(GSCs). Proliferative cells that maintain germ cell production in the adult, often by dividing to produce one self-renewing and one differentiating daughter cell.

Niche

A microenvironment that promotes the maintenance of germline stem cells. The term may refer to the somatic cells that are responsible for creating this microenvironment, or to the physical location in which they reside.

Distal tip cell

A specialized somatic cell comprising the germ cell niche in Caenorhabditis elegans.

Spermatocytes

Male germ cells that have initiated meiosis.

Spermatogenesis

Refers to the entire process of sperm generation from mitotic precursor to mature sperm.

Oogenesis

The process of oocyte generation, from mitotic precursor cell to mature oocyte in meiotic arrest.

Eclosion

The transition from pupa to adult in insects: hatching from the pupal case.

Cap cells

Somatic cells that, together with terminal filament cells and escort cells, make up the germ cell niche in Drosophila melanogaster females. They directly contact germline stem cells and promote stem-cell maintenance.

Hub

The cone-shaped group of somatic cells comprising the germ cell niche in Drosophila melanogaster males.

Cystoblast

A germline stem cell daughter cell that has moved away from the niche and initiated differentiation.

Licensing

A process permitting primordial germ cells to respond to signals promoting meiosis and male or female differentiation.

Prophase

First phase of the meiotic or mitotic cell division (M phase), during which chromosomes condense. In meiosis, prophase occurs before meiosis I and is divided into the leptotene, zygotene, pachytene, diplotene, and diakinesis stages.

Residual body

An anucleate cytoplasmic structure remaining after budding of Caenorhabditis elegans spermatids.

H3.3

A histone H3 variant subunit that is associated with actively transcribed genes as well as with specific heterochromatic regions such as telomeres. Unlike H3.1 and H3.2, deposition is cell-cycle-independent.

Protamines

Highly basic, arginine-rich proteins that replace histones in packaging the genomes of haploid sperm. Packaging with protamines results in highly condensed genomic DNA.

Spermiogenesis

The process of differentiation in haploid sperm after meiosis has been completed, involving nuclear compaction, loss of cytoplasm and generation of a flagellum.

Leptotene

The first stage of meiotic prophase. Chromosomes begin to condense.

Zygotene

The second stage of meiotic prophase. Homologous chromosomes pair.

Pachytene

The third stage of meiotic prophase. Homologous chromosomes are tightly held together by the synaptonemal complex, and homologous recombination ('crossing over') begins.

Diplotene

The fourth stage of meiotic prophase. The synaptonemal complex breaks down, but homologous chromosomes are held together at sites of recombination.

Diakinesis

The final stage of meiotic prophase. Chromosomes condense further, the nuclear envelope breaks down and the meiotic spindle begins to form.

Pronucleus

A term for the nuclei of the male and female gametes after they have formed a single cell at fertilization, before the nuclei have fused.

Epiblast-like stem cells

(EpiSCs). Stem cells that are derived from the epiblast of postimplantation embryos; they exhibit a more restricted differentiation potential than naive embryonic stem cells.

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Lesch, B., Page, D. Genetics of germ cell development. Nat Rev Genet 13, 781–794 (2012). https://doi.org/10.1038/nrg3294

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