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Understanding Images: Animal fertility governed by small non-coding RNAs

Author: Jamy C. Peng, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA

Competing Interests: Jamy C. Peng is an author of the article discussed in this blog.

 

The survival of a species relies on the organism’s ability to produce gametes that can faithfully transmit genetic materials. Fertility of the organism is affected by many factors – one of these is the class of small non-coding RNAs known as Piwi-interacting RNAs, or piRNAs. piRNAs are crucial to the suppression of transposable elements in the germ cells; unchecked activity of transposable elements can result in severe damage to the genome, germ cell death, and infertility. My lab is interested in understanding how piRNAs suppress gene expression and influence fertility beyond their well-known role of transposable element suppression.

piRNAs were discovered just over a decade ago, and sequencing of piRNAs has revealed great complexity, with some organisms containing up to 100,000 different types of piRNA. Intriguingly, some piRNAs were uniquely produced from protein-coding genes and do not contain sequences from transposable elements. We hypothesized that piRNAs may influence the expression of these genes, which in turn might affect germ cell health. To test this hypothesis, we decided to characterize one such protein-coding gene in the fruit fly, Drosophila melanogaster (Figure 1).

Figure 1. Fruit fly. Image Credit: André Karwath, Flickr, CC BY
Figure 1. Fruit fly. Image Credit: André Karwath, Flickr, CC BY

The fruit fly is a great model system to study fundamental processes in biology, and we use its ovary to examine how deregulation of genes by piRNAs influences germ cell health and animal fertility.

One gene we study is c-Fos (also called kayak); a key regulator of cell proliferation that also influences cancer initiation and progression. By using genetic assays, we found that c-Fos interacts with Piwi to affect the germline stem cells of the fruit fly ovary. Germline stem cells give rise to all germ cells, including the eggs themselves that pass genetic materials onto the offspring. Piwi is a master regulator of germline stem cells and a requisite binding partner of piRNAs. By using genomic and biochemical assays, we then determined that the level of c-Fos is actually modulated by piRNAs and Piwi. Our combined results thus suggest a pathway in which Piwi and piRNAs regulate germline stem cells in part by modulating c-Fos level.

Figure 2: Compared to control (left) ovary, c-Fos-overexpressing ovary is much larger due to retention of eggs that have maturation arrest (shown by persistent Green/Vasa expression). Scale bar is 100 micrometer. Image Credit: Jonathon D. Klein and Victoria Frohlich.
Figure 2: Compared to control (left) ovary, c-Fos-overexpressing ovary is much larger due to retention of eggs that have maturation arrest (shown by persistent Green/Vasa expression). Scale bar is 100 micrometer. Image Credit: Jonathon D. Klein and Victoria Frohlich.

The ovary is composed of germ cells and the somatic cells that nurture and provide structural support to the tissue to maintain germline stem cell and normal germ cell development. We found that c-Fos modulation by Piwi and piRNAs is also important for the somatic cells and tissue organization. Overexpression of c-Fos, via either our genetic manipulation or piRNA loss, results in defects in somatic cell organization and ovarian tissue morphogenesis. In the featured image for the September issue of PLOS Genetics, we show that an ovary in which c-Fos is overexpressed accumulates germ cells/eggs that become developmentally arrested, contributing to a much-enlarged tissue volume (Figure 2). This image is important for showing the dramatic tissue enlargement that takes place when a single gene is overexpressed. The animals that carry these c-Fos-overexpressing ovaries contain severely enlarged ovaries and are not able to lay eggs.

Altogether, our data support the idea that piRNAs and Piwi affect germ cell health by regulating genes in addition to inhibiting the activity of transposable elements. Some of these genes are likely to function like c-Fos and to have multi-faceted influences over germline stem cells, the somatic cells that support germ cells, and the tissue organization of the ovaries. Non-transposon gene regulation by piRNAs therefore has important role in regulating animal germ cell health and fertility.

 

Reference

Klein JD, Qu C, Yang X, Fan Y, Tang C, Peng JC (2016) c-Fos Repression by Piwi Regulates Drosophila Ovarian Germline Formation and Tissue Morphogenesis. PLoS Genet 12(9): e1006281. doi:10.1371/journal.pgen.1006281

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