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Patricia A. Martin-DeLeon, Trustees Distinguished Professor of Biological Sciences at UD, studies fertility in mice, the closest genetic model to humans.
We dont know if a sperm actually
experiences joy when it finally finds the egg, but it does wiggle
Patricia A. Martin-DeLeon, a reproductive biologist at the University
of Delaware, has witnessed this behavior many times in her studies of
fertility in mice, the closest genetic model to humans (and with a much
faster reproductive cycle).
Its what happens next in the fertilization process that DeLeon and
her team have revealed for the first time, which could help couples
struggling with infertility.
There is communication between the sperm and the fallopian tube that
helps prepare the sperm for its big push into the egg, says DeLeon,
who is the Trustees Distinguished Professor of Biological Sciences at UD.
The research, supported by the National Institutes of Health-National Institute of Child Health and Human Development and the Delaware INBRE program, is published in the Journal of Biological Chemistry.
It is one of the top most viewed articles published online this summer
under the Membrane Biology affinity group, according to the editorial
offices of the American Society for Biochemistry and Molecular Biology.
Understanding what happens in the fertilization process takes a
little walk down biological memory lane, a reminder of natures course
that led to most of us.
Once the egg is released from an ovary and enters the Fallopian tube,
the hair-like cilia that line this tiny tube sweep the egg toward the
uterus. While in the tube, the egg will either meet the sperm and be
fertilized, which must happen within a 12- to 24-hour window of time, or
fertilization will not occur and the egg will dissolve.
Hormones trigger the release of these oviductosomes, which are only
100 nanometers in diameter, or about 10 millionths of an inch wide. The
tiny cargo-filled sacs then attach to the sperm like decorations on a
Christmas tree before the sperm fuses with the egg.
Once these sacs are in place, they transfer proteins, including a
calcium clearance pump (scientifically known as Plasma Membrane Ca2+-ATPase 4), to the sperm for use when the time is right.
This calcium pump is required by the sperm just prior to
fertilization, as well as in the early embryo, DeLeon says. The sperm
pumps out calcium and takes in hydrogen ions, which seems to give it
that last push into the egg, and also is critical to starting the
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The green signal shows the presence of the "calcium clearance pump." The red arrow shows an oviductosome without the pump, while the yellow arrow shows one carrying the pump. These observations provide evidence that oviductosomes carry different cargoes to the sperm, which need the pump to reduce calcium levels quickly or risk DNA damage.
DeLeon and her team made their discovery using the high-powered, three-dimensional super-resolution microscope that UD acquired in 2012.
The technology, whose inventors won the Nobel Prize in 2014, can
illuminate whats happening in a cell, right down to a single molecule.
The oviductosomes from a female mouse were pre-labeled with a
fluorescent dye and incubated together with the sperm. Within an hour,
the oviductosomes were fused to the sperms surface. After two to three
hours, the oviductosomes continued to accumulate, primarily on the
sperms head and the midpiece of its tail.
Integrins, which are membrane receptors on both the sperm and the
oviductosomes, helped to facilitate their bonding, along with fusion
stalks on the sperms surface.
Discovery of these oviductosomes provides us with a window into the
cargo being delivered by the female to the sperm, DeLeon says. The
implication is that we could improve IVF with this knowledge.
IVF, or in vitro fertilization, currently has a 32 percent success
rate, and couples for whom the procedure fails face the puzzling,
disappointing reality that they cant have a child of their own. Even
when the process works, a high sperm-to-egg ratio is required, the
opposite of what occurs in the body.
Weve shown that these oviductosomes are carrying critical molecules
that include not only proteins, but also nucleic acids such as RNA and
also lipids, DeLeon says. That gives us hope they can be used as
vehicles for improving fertility and the chances of producing healthy
embryos and offspring.
Currently, DeLeon and her team are analyzing the protein-rich
contents of this cargo to find out exactly what gives the sperm what it
needs for its last push to penetrate the egg always head first, tail
out to fertilize it.
As for the calcium clearance pump, the sperm needs to use it to
reduce toxic calcium levels quickly. Otherwise, the sperm risks a
buildup of nitric oxide, which can cause DNA damage.
Our work may lead to the discovery of genes and gene products that
cause infertility, DeLeon says of the teams continuing research. We
may identify proteins required to improve the efficiency of IVF, and
improve the outcome and health of the offspring. Its really another
step in the direction of personalized medicine, since individuals
carrying mutations of one of a variety of genes account for the largest
group of infertile couples.
DeLeon has been making major contributions to reproductive science
since she published her first scientific article Cannabis and
Chromosomes, examining the impact of marijuana on embryonic cells in The Lancet in 1969, as a masters student at the University of the West Indies in her native Jamaica.
The response to that paper was so dramatic, with requests for copies
from scientists around the world, that DeLeon set her sights on a career
in research and teaching and never looked back, continuing on for her
doctorate at the University of Western Ontario. She joined the UD
faculty in 1976.
DeLeons co-authors on the study include Amal A. Al-Dossary, who
graduated with her doctorate from UD last December and is now a
professor at the University of Dammam in Saudi Arabia; Pradeepthi
Bathala, who is pursuing her masters degree at UD; and Jeffrey Caplan,
director of the BioImaging Center at the Delaware Biotechnology
About the research sponsors:
Part of the National Institutes of Health (NIH), the National
Institute of Child Health and Human Development has primary
responsibility for conducting and supporting basic, translational, and
clinical research in the biomedical, behavioral, and social sciences
related to child and maternal health, in medical rehabilitation and in
the reproductive sciences.
The Delaware IDeA Network of Biomedical Research Excellence (INBRE)
is funded by a grant from the NIH-National Institute of General Medical
Sciences and by the state of Delaware to continue building a
self-sustaining basic and translational biomedical research capability