The Ly6/uPAR protein Bouncer is necessary and sufficient for species-specific fertilization
Preprint posted on June 24, 2018 https://www.biorxiv.org/content/early/2018/06/24/354688
Scientists mostly ignore the massive number of short open reading frames present across the transcriptome. Too small to do anything useful, right? Do they even code for proteins? But recently several groups have begun to examine these tiny proteins, and uncovered a hidden universe of fascinating functions. The lab of Dr. Andrea Pauli has previously described functions for small proteins in the zebrafish embryo, for example the secreted protein Toddler / ELABELA, which is required for mesodermal cell migration. Now the lab is on the hunt for more little genes with big functions.
Mining a variety of whole genome datasets [disclosure: I helped to generate some of these datasets when Dr. Pauli and I were postdocs], Herberg et al. identified another small gene missing from the annotated zebrafish genome. For reasons described below, the authors named this gene bouncer. This gene was highly expressed in oocytes and predicted to code for a 125 amino acid protein. This protein contains domains that suggest it is processed, transported and anchored to the egg membrane. The authors confirm that the protein is localized and anchored to the egg membrane, and set out on a journey to discover why.
They made bouncer mutant zebrafish, and found that while male mutants were viable and fertile, adult female mutants produced eggs that are morphologically normal but could not be fertilized. However, when they directly injected sperm into the egg, the resulting zygotes began normal cell divisions. This result suggested that Bouncer was important for sperm entry into the egg. Hinting at mechanism, gently washing of mutant eggs (but not wild-type eggs) with sperm bound was enough to dislodge the sperm. Based on this evidence, the authors suggest that Bouncer is part of the complex that captures sperm at the micropyle, the sperm entry point into the egg.
So why is it called Bouncer? In the most shocking experiment of the whole story, the authors test whether this protein mediates species specificity between sperm and egg. In most cases, sperm from one species can only successfully fertilize eggs from the same species. Interactions between sperm and egg often dictate this specificity, through mechanisms that are still being discovered. When the authors replaced zebrafish Bouncer with Bouncer from another fish species (medaka), suddenly medaka sperm could fertilize zebrafish eggs! These hybrid embryos go through early cleavage stages and at least some phases of gastrulation. Hence the name: a protein required and sufficient for sperm entry is similar to the doorman at a club – the “bouncer.” This experiment is astonishing for several reasons, for example, these two species of fish are 150 million years apart, further apart in evolutionary time than humans and mice. It is also surprising that only a single egg protein is sufficient for species-specific sperm entry, a seemingly risky gatekeeping strategy.
In summary, this manuscript describes the role of a small protein required for species-specific fertilization – Bouncer only lets the “right” sperm into the egg. This manuscript suggests several paths for future research, from uncovering the mysteries of Bouncer / sperm interactions, to discovering what happens to those fertilized hybrid embryos. Finally, this reader wonders how many other small genes still remain to be discovered by those who know how to look.
- From the hybrid experiment, it seems that Bouncer may directly bind to sperm. What proteins are on the sperm side of the “velvet rope”?
- Speaking of mechanism: What residues on the Bouncer are required for species specificity, and are there any predictions from related protein structures? And how does Bouncer gets to the micropyle?
- Amazingly, a tiny fraction (0.11%) of bouncer mutant eggs did get fertilized – can these fish survive to adulthood? Are they fertile? Is there a compensatory mechanism?
- Do the hybrids express medaka genes? Why and when do the hybrids die?
Posted on: 5th July 2018Read preprint
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