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Movement of sperm to the egg

Movement of sperm to the egg


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Sperm swims through semen and reaches the haploid egg in the oviduct during fertilisation.

  • Once the sperm reaches the cervix, through what does the sperm swim through to reach the egg?

  • Is the uterus completely filled with a fluid that allows the movement of the sperm, or does the sperm only swim through the endometrium (uterine lining)?


Once the sperm reaches the cervix, through what does the sperm swim through to reach the egg?

It swims through the cervical mucus. Human sperm swim in a straight path in cervical mucus.

Is the uterus completely filled with a fluid that allows the movement of the sperm, or does the sperm only swim through the endometrium (uterine lining)?

Yes, the uterus is completely filled with uterine fluid. They are attacked by many leukocytes while being helped by various contractions.

I would suggest reading the Suarez 2006 review. It has very nice information of all stages of sperm moment.


A Stroke of Genius: New Research Shows That Sperm Don’t Slither—They Corkscrew

By 1677, Antonie van Leeuwenhoek had already begun to shape his legacy as the “father of microbiology.” In addition to constructing his own microscopes, the mostly self-taught scientist was the first to study microorganisms in pond water, calling them animalcules. So when a medical student named Johan Ham observed something that appeared to be alive in a human semen specimen, he brought it to van Leeuwenhoek.

Through the microscope lens, van Leeuwenhoek saw it, too: a “small earth-nut with a long tail” that we now know as sperm. After examining some of his own specimens, van Leeuwenhoek asserted that sperm propel themselves forward with “the motion of their tails like that of a snake or an eel swimming in water.”

For nearly 350 years, scientists have supported van Leeuwenhoek’s claim that human sperm move through liquid by lashing their tails from side to side. But a new study published in Science Advances shows that these cheeky little earth-nuts don’t slither like eels at all. Instead, they corkscrew like otters.

A group of researchers from the UK and Mexico used a high-speed camera and other microscopy devices to capture a sperm’s movement in 3D, which revealed that its tail actually only lashes to one side—and if you’ve ever tried to row a boat with one oar, you probably know that sticking to one side will send you spinning in circles. The sperm, however, have figured out a clever fix. They rotate their bodies every time their tails strike sideways, which pushes them forward in a corkscrew motion.

The reason van Leeuwenhoek’s original observation went undisputed for so long is mainly because scientists have continued to view sperm with 2D technology. Without depth, you can’t tell that the sperm’s body is spinning, and the tail looks like it’s simply moving to each side, rather than completing a rotation. And as Hermes Gadêlha, University of Bristol lecturer and co-author of this study, explained in his article for The Conversation, sperm’s size and speed make them hard to observe closely. In less than one second, they can complete about 20 propulsions.

While this study is significant for the mere shock factor of realizing we’ve been wrong for centuries, it could also impact future research on the causes of male infertility. In other words, having a better understanding of how sperm travel to eggs may help us understand why some make it there more easily than others.


A mosquito sperm's journey from male ejaculate to egg: Mechanisms, molecules, and methods for exploration

The fate of mosquito sperm in the female reproductive tract has been addressed sporadically and incompletely, resulting in significant gaps in our understanding of sperm-female interactions that ultimately lead to fertilization. As with other Diptera, mosquito sperm have a complex journey to their ultimate destination, the egg. After copulation, sperm spend a short time at the site of insemination where they are hyperactivated and quickly congregate near the entrance of the spermathecal ducts. Within minutes, they travel up the narrow ducts to the spermathecae, likely through the combined efforts of female transport and sperm locomotion. The female nourishes sperm and maintains them in these permanent storage organs for her entire life. When she is ready, the female coordinates the release of sperm with ovulation, and the descending egg is fertilized. Although this process has been well studied via microscopy, many questions remain regarding the molecular processes that coordinate sperm motility, movement through the reproductive tract, maintenance, and usage. In this review, we describe the current understanding of a mosquito sperm's journey to the egg, highlighting gaps in our knowledge of mosquito reproductive biology. Where insufficient information is available in mosquitoes, we describe analogous processes in other organisms, such as Drosophila melanogaster, as a basis for comparison, and we suggest future areas of research that will illuminate how sperm successfully traverse the female reproductive tract. Such studies may yield molecular targets that could be manipulated to control populations of vector species. Mol. Reprod. Dev. 83: 897-911, 2016 © 2016 Wiley Periodicals, Inc.

© 2016 Wiley Periodicals, Inc.

Figures

Typical reproductive tract of female…

Typical reproductive tract of female Culicinae mosquitoes. A : Simplified sagittal diagram with…

Frame‐by‐frame model of sperm path…

Frame‐by‐frame model of sperm path through Culicinae female reproductive tract from insemination (…

Sagittal section of the Aedes…

Sagittal section of the Aedes aegypti female reproductive tract (Jobling and Lewis, 1987).…

Analog of Figure 2, with text indicating unexplored, under‐studied, and poorly understood aspects…


Researchers Discover How Human Sperm Really Swim

In 1677 Anton van Leeuwenhoek, Dutch scientist and inventor of the first compound microscope, finally gave into peer pressure from his colleagues and used the tool to examine his own semen. The wriggling “animalcules” that he described would come to be known as individual sperm cells, or spermatozoa. Each had a rounded head and, van Leeuwenhoek thought, a tail that moved side to side to project it through fluid. Until now, pretty much everything scientists know about human sperm movement has been based on van Leeuwenhoek’s primitive observations. But a paper published today in Science Advances has upended roughly 350 years’ worth of assumptions about reproduction, the most essential of biological functions.

“There's just complete misinformation in almost the entire history of understanding sperm functional biology, and it needs to be corrected, but it's a real challenge,” says Scott Pitnick, an evolutionary biologist who studies sperm biology at Syracuse University and who was not involved in the study. “And this is one of the first studies that has really risen to that challenge and cracked sort of a complex problem.”

Using 3-D microscopy and advanced mathematical analyses, an international team of researchers from the University of Bristol in England and the Universidad Nacional Autonoma de Mexico discovered that the human sperm tails’ snakelike movement is an optical illusion. Rather than moving side-to-side, sperm tails actually turn in only one direction. Without other adjustments, a one-sided stroke would result in sperm swimming in circles and never reaching their destination, the female egg. To compensate, the scientists found, the body or head of the sperm rotates independently in a corkscrew-like motion in the opposite direction, enabling the whole cell to move forward in a straight line.

“We were not expecting to find what we found,” says Hermes Gadêlha, head of the Polymaths Lab at University of Bristol and lead author on the study. “The aim of the project was ‘blue sky’ [or broad] research, to understand how sperm moves in three dimensions. And the result has completely changed the belief system that we have.”

The limitations of van Leeuwenhoek’s description of sperm motility were no fault of his own he was using the most advanced technology available at the time. “To see the true movement, you would have to swim with the cell, and the way you do this, is almost like if you could get a GoPro camera and attach it to the head of the sperm, and look at the tail,” says Gadêlha.

To get an accurate picture of how a sperm cell moves, Gadêlha and his team vertically suspended sperm in a solution. They set the sperm solution in a stabilized 3-D microscope to scan for motion as a high-speed camera recorded more than 55,000 frames per second at many angles. They also attached a piezoelectric device—which measures changes in pressure, acceleration, and force by converting these properties to electrical charges—to the 3-D microscope. That device gathered information about sperm movement at the level of submicron resolution, smaller than one-millionth of a meter. By running the combined data gathered from all the machines through advanced mathematical transformations, the scientists were able to find movement averages and “see” the true directionality of the tails.

Each sperm cell moved like a spinning top, rotating around its own axis, and also around a middle axis. “What nature is telling us is that there is more than one way to achieve symmetry,” says Gadêlha. “Sperm use asymmetry to create symmetry.”

Human spermatozoa are not the only microorganisms to function this way—mouse and rat sperm and the flagella of Chlamydomonas, a type of green algae, also have asymmetric movements and an underlying asymmetric shape. This, says Gadêlha, may be indicative of universality in organizational structures across species.

Whether or not a sperm’s movement is the most efficient way to swim is hard to quantify. “We like to think that nature is optimizing things but we always have to remember that there are many competing aspects. A sperm cell is not just made to swim and find the egg, it has to find chemical cues, react to different viscosities, activate,” says Gadêlha. “At every stage you need a new super power that enables you to do these things.”

To understand the evolution of structural mechanisms within an organism, Pitnick says, it’s about understanding the familiar biological concept of form fitting function the shape of something is designed for the job it is meant to perform. To truly understand sperm, it must be observed in its intended, selective environment—the female reproductive tract, which scientists also need to study more. “The female is a complex three-dimensional environment.,” says Pitnick. “And we don't know very much about it, and in part that's just been a historical, obscene male bias in doing biology.”

Sperm tail moves asymmetrically, wiggling the tail to one side only. This causes the sperm to spin in 3D. (polymaths-lab.com)

Doctors think that this new discovery showing how sperm move can help treat infertility, a condition that affects roughly 50 million couples globally. Male biological factors are solely responsible for an average of 20 to 30 percent of cases of infertility, and contribute to about 50 percent over all. Still, these statistics are biased based on countries where data from IVF and other fertility treatments are common, so sperm factors could be even more significant than recorded. “[Male infertility] is really quite common, perhaps more common than the general public realizes,” says Cori Tanrikut, a reproductive urologist with Shady Grove Fertility Center in Maryland. “And right now, if you want to think about this study, currently, we really have limited means of improving or optimizing sperm motility.”

The more accurately scientists can understand the fundamental molecular biology of sperm motility, the better doctors may be able to address motility issues associated with infertility, says Tanrikut. She hopes that knowledge gained from future work in the field will help her offer patients less aggressive fertility treatment options, or even improve their chances of conceiving without assistance.

Implications of Gadêlha and his team’s discovery could also go far beyond the scope of what this study demonstrates about sperm. The cell as an organism makes unconscious computations and corrections, adjusting torque and movement patterns depending on the conditions around it. Understanding these mechanisms could inform soft robotics research and materials science. One of Gadêlha’s students, for example, is looking at how the body’s slight, undetectable oscillations could be useful in developing foot and ankle prosthetics.

About Courtney Sexton

Courtney Sexton, a writer and researcher based in Washington, DC, studies human-animal interactions. She is a 2020 AAAS Mass Media Fellow and the co-founder and director of The Inner Loop, a nonprofit organization for writers.


Enzyme Essential To Sperm Movement Provides Target For New Contraceptive Approach

A team of researchers has determined that an enzyme in sperm is necessary for sperm movement. Mice bred to lack this enzyme produce sperm that cannot swim toward egg cells to fertilize them.

The enzyme, known as GAPDS, is essentially the same as an enzyme produced in human sperm. The researchers believe that designing a drug to disable the enzyme might provide the basis for an effective new form of male contraception. Similarly, an understanding of the enzyme and related chemical reactions might lead to insights into treatment for some forms of male infertility.

"Currently, attempts to design a male contraceptive involve manipulating male hormones," said Duane Alexander, M.D., Director of the NICHD. "This finding provides a promising new lead that might allow development of a contraceptive that targets only sperm and doesn't affect natural hormone levels."

Enzymes are chemical compounds that assist a chemical reaction.

The study was funded by the National Institute of Child Health and Human Development of the National Institutes of Health, and will appear in the Proceedings of the National Academy of Sciences Online Early Edition the week of November 15, 2004.

GAPDS, short for Glyceraldehyde 3-phosphate dehydrogenase-S, is a key enzyme in a series of biochemical reactions known as glycolysis. This series of reactions produces ATP, a kind of cellular fuel that supplies energy for the cell's activities. GAPDS is found only in sperm (the final "S" in the acronym stands for sperm) and the precursor cells that give rise to sperm. However, a related enzyme is present in virtually all the cells in the body.

GAPDS is found in the sperm's flagellum, the snake-like tail which whips back and forth to propel the sperm forward. In earlier studies, researchers found that glycolysis played a role in sperm movement, but did not know how much of the total amount of ATP in sperm resulted from glycolysis. Before the current study, most researchers believed that most of the ATP for the tail's movement came largely from cellular bodies called mitochondria, which are thought to generate more ATP than does glycolysis.

In the current study, Dr. Deborah O'Brien, Ph.D., of the University of North Carolina School of Medicine at Chapel Hill and her colleagues sought to determine if sperm require GAPDS and glycolysis in order to move forward and fertilize eggs. Using molecular genetic techniques, they generated a strain of mice that were genetically incapable of producing GAPDS. Although the mice mated normally with receptive female mice, the females did not become pregnant. When the researchers examined sperm from the mice under a microscope, the sperm showed only a slight side-to-side movement, but were incapable of moving forward.

"We were very surprised at this finding," Dr. O'Brien said. "It turned out that almost all of the sperm's motility and ATP production depended on this enzyme."

At this point, the researchers know that sperm lacking GAPDS can not swim forward toward the egg, but they did not conduct studies to determine whether the GAPDS-deficient sperm could fertilize eggs with which they are placed in contact.

Dr. O'Brien's study was funded as part of NICHD's Specialized Cooperative Centers Program in Reproduction Research, which seeks to identify compounds that might provide the basis for new forms of contraception and provide insights that might be helpful in treating infertility.

The human form of GAPDS is known as GAPD2, explained Louis De Paolo, Ph.D., of NICHD's Reproductive Sciences Branch, administrator of the Specialized Centers Program. A drug that interfered with the enzyme might provide an effective means of nonhormonal male contraception.

One possibility, he added, would be a drug that males could take to interfere with sperm motility. Another possibility would be a drug that could be deposited in the female reproductive tract, which could stop the movement of sperm when they come in contact with it.

Dr. De Paolo noted that current attempts to design a male contraceptive pill involve drugs that temporarily halt the functioning of the testes. These drugs not only suppress sperm production, but also the production of the male hormone testosterone, necessary for normal reproductive functioning. Such treatments typically involve replacing the missing testosterone through artificial means &mdash a process that could increase the risk for prostate cancer. A drug that interfered with GAPD2 would leave testosterone levels unaffected, he said.

Similarly, studying the functioning of GAPD2 might provide insights that could lead to treatments for male infertility.

"One study showed that in a sample of infertile men, about 81 percent had sperm with defects in motility," Dr. De Paolo said.

Some of these men might have a genetic defect that interferes with normal production of GAPD2, he added. A drug that restored GAPD2 functioning might provide a treatment for their infertility. Similar molecular defects in the glycolysis pathway that produces ATP might also interfere with sperm movement, and might be the focus of other treatments.

"This finding has opened up several exciting new possibilities for future studies of male fertility regulation," he said.


Birds require multiple sperm to penetrate eggs to ensure normal embryo development

Unlike humans, birds require multiple sperm to penetrate an egg to enable their chicks to develop normally.

A new study by scientists at the University of Sheffield revealed there is a functional role for 'extra' sperm in the early stages of embryo development. This is very different to humans and other mammals where the entry of more than one sperm into an egg is lethal.

Researchers also discovered female birds are able to regulate the number of sperm that make it to the egg, ensuring that sufficient sperm are available for fertilisation -- particularly when the numbers of inseminated sperm are limited.

The study, led by Dr Nicola Hemmings from the University's Department of Animal and Plant Sciences, gives an insight into the biological significance of polyspermy which is a major puzzle in reproductive biology.

It has been a long-standing question in the natural world whether the extra sperm that enter a bird's egg have any role to play in fertilisation or early embryo development. The pioneering research shows that when very few sperm penetrate a bird's egg, the embryo is unlikely to survive.

Dr Hemmings explained: "Our research shows that, in contrast to humans and other mammals, one sperm is not enough to ensure normal embryo development in birds.

"When just a single sperm enters the bird egg, fertilisation may occur normally, but the resulting embryo will probably die at a very early stage. This is surprising because when more than one sperm enters the human or mammalian egg -- a process we call polyspermy -- the egg is destroyed.

"Polyspermy has generally been considered to be bad for reproduction, but our results suggest that, in certain animal groups, polyspermy may in fact be necessary."

The research is published today (Wednesday 28 October 2015) in the journal Proceedings of the Royal Society B.

Dr Hemmings added: "These findings provide an exciting expansion of our view of the sperm's role in fertilisation. It is fascinating to speculate how the 'extra' sperm contribute to the early stages of embryo formation and development."


This article was interesting to me because I had never given any thought to the fact that the way in which reproductive biology is being taught parallels the stereotypical way that men and women are portrayed. One paragraph in Emily Martin’s article “The Egg and the Sperm” that really stood out to me was:

“Degeneration continues throughout a woman’s life: by puberty 300,000 eggs remain, and only a few are present by menopause. “During the 40 or so years of a woman’s reproductive life, only 400 to 500 eggs will have been released,” the authors write. “All the rest will have degenerated. It is still a mystery why so many eggs are formed only to die in the ovaries.”” The real mystery is why the male’s vast production of sperm is not seen as wasteful. Assuming that a man “produces” 100million (10’) sperm per day (a conservative estimate) during an average reproductive life of sixty years, he would produce well over two trillion sperm in his lifetime. Assuming that a woman “ripens” one egg per lunar month, or thirteen per year, over the course of her forty-year reproductive life, she would total five hundred eggs in her lifetime. But the word “waste” implies an excess, too much produced. Assuming two or three offspring, for every baby a woman produces, she wastes only around two hundred eggs. For every baby a man produces, he wastes more than one trillion (10 12 ) sperm.”

I think this paragraph is important because one of the elements of the article that it points out is that women and their bodies are inferior to men. The example that this uses in relation to reproductive biology is that a woman has a certain number of eggs by the time puberty rolls around. During a woman’s reproductive life, only a tiny fraction of these will be released, and only several will actually develop into a child, depending on how many children she has. With men, there are millions and millions of sperm that are “wasted”. Yet, it is the women who are seen as the ones being wasteful with their eggs. While women’s eggs are the ones that actually have the more lengthy process of developing into a human being, they are the ones that are deemed inferior. I don’t think it is intentional that women and their bodies are being described as less important or negative. However, the fact is they are being described as inferior, and I just wonder if that point could be mentioned in the textbooks. I also think equality and accuracy of the processes should be stressed.

A thought that this paragraph brought up was abortion, and the debate over that issue right now. This paragraph was saying that an egg or a sperm are “wasted” if they’re not joined and fertilized, implying that life begins at conception. I think this paragraph could be challenged by asking, when exactly does life begin, and are they really being wasted if life is considered to being after the first trimester, or whatever it might be. My personal view is that, if eggs and sperm don’t meet and form into a child, I don’t really consider that to be wasteful. I don’t think our bodies and sex were designed simply for reproduction. I’m not sure why approximately one trillion sperm are in an emission of semen and only one alone is needed to create life. I also don’t know why an egg is released from an ovary every single month, but only a few MAY be used for pregnancy. But if these cells were really just completely wasted, I don’t think our bodies would work like that.

Another paragraph that stood out was:

“In this recent investigation, the researchers began to ask questions about the mechanical force of the sperm’s tail. (The lab’s goal was to develop a contraceptive that worked topically on sperm.) They discovered, to their great surprise, that the forward thrust of sperm is extremely weak, which contradicts the assumption that sperm are forceful penetrators.4O Rather than thrusting forward, the sperm’s head was now seen to move mostly back and forth. The sideways motion of the sperm’s tail makes the head move sideways with a force that is ten times stronger than its forward movement. So even if the overall force of the sperm were strong enough to mechanically break the zona, most of its force would be directed sideways rather than forward. In fact, its strongest tendency, by tenfold, is to escape by attempting to pry itself off the egg. Sperm, then, must be exceptionally efficient at escaping from any cell surface they contact. And the surface of the egg must be designed to trap the sperm and prevent their escape. Otherwise, few if any sperm would reach the egg.”

First of all, I was surprised that whoever did this research was THAT concerned about who is being better represented (men or women), that they looked this deep into how sperm moves. It was probably originally done just to see how to process worked, but regardless, someone looked so deep into it, and compared it to how men and women are seen in society. However, I’m glad they did. I think this paragraph encompasses a view that represents the strength of women, and how us and what we have to offer. In this case, an egg that stands up to the sperm and doesn’t just passively let it penetrate it.

I was confused by the fact that the article said that the sperm’s “strongest tendency, by tenfold, is to escape by attempting to pry itself off the egg”. This confused me because I wasn’t sure how it related to men/women dynamics. It made the women side of things seem extra powerful and dominating, which is a more masculine trait. I understand that they were trying to point out that the egg, or women, aren’t these weak parts that don’t matter. However, I guess I thought that it was supposed to point out that we are equal. I feel like no matter what side you take on gender issues, one is always being portrayed as better or more powerful than the other. I think we were created to be equals, and we just aren’t being depicted as that.

Overall, I liked the article. It was easy to read, and I had never seen reproductive biology portrayed in quite that way before, and had never thought about it like that. I thought it was interesting to see the issue in that way, and dig into how our reproductive processes should be taught and talked about.


Study Information

Study published on: July 31, 2020

Study author(s): Hermes Gadêlha, Paul Hernández-Herrera, Fernando Montoya, Alberto Darszon, and Gabriel Corkidi

The study was done at: University of Bristol & Universidad Nacional Autónoma de México

The study was funded by: H.G. and P.H.-H. acknowledge support from Dirección General de Asuntos del Personal Académico PREI/UNAM DGAP/DFA/2337/2018 and scholarship CJIC/CTIC/0961/2019. H.G. acknowledges support from DTP EPSRC. G.C. and A.D. acknowledge financial support from the Consejo Nacional de Ciencia y Tecnología Conacyt 253952, 255914, and Fronteras 71.

Raw data availability: Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors. https://advances.sciencemag.org/content/6/31/eaba5168/tab-figures-data

Featured image credit: Image by Gerd Altmann from Pixabay


When sperm meets egg

Sperm–egg binding is mediated by two cell-surface proteins. Structural analysis of these proteins separately and in complex provides insight into the recognition process and the subsequent sperm–egg fusion. See Letters p.562 & p.566

An interaction between two proteins — Izumo1, which is produced by sperm, and Juno, its receptor on eggs — enables human fertilization. However, the details of this interaction have been elusive. In two papers, Aydin et al. 1 (page 562) and Ohto et al. 2 (page 566) present the structures of Izumo1, Juno and the two proteins in complex, determined by X-ray crystallography at atomic-level resolution.

Following human copulation, motile sperm move towards eggs in the female's Fallopian tubes. The acidic environment of the female reproductive tract triggers an activation step, in which sperm become hypermobile and penetrate the outer protective layer of the egg. A second activation step occurs when or shortly before the sperm binds to the zona pellucida — the tough inner layer that surrounds the egg. During this step, the acrosome — an organelle at the tip of the sperm head — releases digestive enzymes that break down the zona pellucida. This acrosome reaction allows the sperm to bind to Juno on the egg membrane, following which the two cells' membranes fuse and the cells merge. In turn, the egg releases enzymes that crosslink glycoproteins of the zona pellucida to make it impenetrable, preventing fertilization by multiple sperm (polyspermy) 3,4 .

Izumo1, which is named after a Japanese marriage shrine, was first identified in 2005 by its binding to an antibody that blocked sperm–egg fusion 5 . The protein remains concealed intracellularly in the inner acrosomal membrane until the acrosome reaction occurs, when the inner membrane becomes part of the cell surface. Juno, named after the Roman goddess of love and marriage, was identified almost a decade later 6 as a membrane-anchored protein that is required for female fertility, sperm–egg membrane fusion, and egg binding by Izumo1. One structure of mouse Juno has been published this year 7 , and another will soon be published in Nature Communications 8 . But structures of the extracellular domain of Izumo1, human Juno and the Juno–Izumo1 complex have remained unknown.

Juno was originally called folate receptor-δ, and shares close to 60% amino-acid identity with human folate receptors 6 (receptors for folic acid and its derivatives). The structures of Juno from mice 7,8 and the current studies reveal that the protein has an almost identical fold to that of folate receptors 9,10 : globular, stabilized by eight disulfide bonds (S–S) and with a deep, ligand-binding pocket. But several key amino-acid residues in Juno's ligand-binding pocket differ from those of the folate receptors, consistent with the fact that Juno cannot bind folates 4 .

Both groups find that the extracellular region of Izumo1 has two domains — a four-helix bundle at the protein's amino terminus and an immunoglobulin-like domain at the carboxy terminus. The two domains are connected by a hinge region consisting of a β-hairpin structure with loops at either end that are anchored to the two folded domains by disulfide bonds. The researchers show that Izumo1 and Juno form a high-affinity complex in a 1:1 ratio. A surface of Juno distant from the pocket binds the outside of the hinge and makes contacts with both Izumo1 domains (Fig. 1).

Aydin et al. 1 and Ohto et al. 2 have solved the structures of the human sperm protein Izumo1 and its egg receptor Juno. Izumo1 is shown in ribbon form and Juno in a surface representation. Izumo1 consists of two folded domains on either side of a connecting hinge (orange). When Izumo1 is in its free state, the hinge is more flexible and may allow the protein to adopt more-bent conformations than when it is bound to Juno (possible conformation change indicated by black arrow). Juno binding stabilizes the hinge, fixing it in an elongated conformation. This might expose disulfide bonds (S–S yellow) for disulfide-exchange reactions to promote Izumo1 dimerization and subsequent sperm–egg membrane fusion.

Ohto and colleagues crystallized structures of free and Juno-bound Izumo1 in the same elongated conformation. By contrast, Aydin et al. report that Izumo1 alone adopts a boomerang-shaped conformation, in which the hinge is almost 40° more closed than that of Juno-bound Izumo1. The authors validated the approximate shape using a technique known as small-angle X-ray scattering. This provides low-resolution structural information about the protein in solution, thereby avoiding potential conformational biases that can arise in X-ray crystallography owing to crystal packing. These data indicate that the boomerang-shaped conformation is probably the predominant conformation of Izumo1 in solution. Moreover, although Juno binds to the outer hinge surface, the region most strongly stabilized by this binding seems to be inside the hinge. This suggests that the hinge can adopt different positions in Izumo1 alone, but that Juno fixes the conformation of Izumo1 by simultaneously binding to both domains.

Although binding interfaces are typically the most evolutionarily conserved surfaces of proteins, the Izumo1–Juno interface is less conserved than the remainder of either protein. Both groups suggest that variation at the binding surfaces might contribute to species specificity during fertilization, because sperm–egg fusions retain some specificity even if the zona pellucida (the main block to cross-species fertilization) is removed 11 . Ohto and colleagues introduced genetic mutations into mouse Izumo1 that strongly reduced the affinity of the Izumo1–Juno interaction. Expression of wild-type Izumo1 in monkey kidney cells (which do not normally express Izumo1) enabled these cells to bind efficiently to mouse eggs that lacked the zona pellucida, whereas cells that expressed the mutant protein could not. These results clearly confirm the interface identified in these structures and its importance in mediating sperm–egg docking.

Why would a protein-binding receptor evolve from a folate receptor? It is tempting to speculate that an unidentified, non-folate ligand might bind the pocket of Juno to modulate the receptor's activity. Folate receptors are exquisitely pH-sensitive and release folic acid under acidic conditions 10 , and Ohto et al. demonstrated that slight acidification drastically decreased Juno's affinity for Izumo1. Together, ligand binding and pH changes could enable Juno to regulate Izumo1 binding at multiple levels.

Although the interaction between Izumo1 and Juno in sperm–egg recognition and adhesion has been structurally and biophysically characterized, the transition from initial binding to membrane fusion remains unclear. Izumo1 stays in the membrane following binding, whereas Juno is shed. This shedding might rapidly block polyspermy before the slow hardening of the zona pellucida is completed 6 . Previous work 12 suggests that Izumo1 undergoes stable dimerization through a disulfide-exchange reaction, dissociating from Juno to enable recruitment of membrane-fusion machinery. Indeed, Ohto et al. provide evidence that the disulfide bonds in Izumo1 are easily broken — perhaps stabilization of Izumo1 following Juno binding could expose disulfides for exchange. Testing this hypothesis and determining how Izumo1–Juno binding triggers membrane fusion will require the identification of proteins that bind to Izumo1 after Juno shedding, and the reconstitution of events that follow initial binding in cells. Footnote 1


Movement of sperm to the egg - Biology

For fertilisation, millions of sperm cells race toward the egg by rhythmically wagging their tail. How they head to the goal straight is unknown. A new study reveals that a chemical modification on proteins controls the sperm tail’s behaviour, and in its absence, amazingly, sperm turns to swim circularly, rather than to swim straight toward the egg, causing defects in male fertility.

Credits: ParallelVision – Pixabay

Sudarshan Gadadhar is Postdoctoral Research Fellow at Institut Curie, Université Paris sciences et lettres, CNRS UMR3348, Orsay, France.

Sudarshan Gadadhar is also an author of the original article

Carsten Janke is Professor at Université Paris-Saclay, CNRS UMR3348, Orsay, France.

Carsten Janke is also an author of the original article

In-house Scientific Editor

Mammalian fertilisation is a dynamic, spectacular event. Millions of sperm race toward the egg, and only one winner can eventually fuse with it and lead to a new life. A sperm is a special type of cell with a tail-like appendage (named flagellum) allowing it to swim straight (imagine how a tadpole swims!). In a new study, we asked how a sperm heads to the goal straight.

Rhythmic movements of the sperm tail are driven by elongated stretches of protein filaments called cytoskeleton. Like the human skeleton forms the basic shape of our body, the cytoskeleton defines the shape of the cell. Beyond being an architectural framework, microtubules – key components of the cytoskeleton – help the sperm wag its tail and move forward by using in-house 'motor' proteins called dyneins. Dyneins can convert chemical energy into mechanical force, and they can do this locally by 'walking' along elongated microtubule fibres. Thousands of dyneins walk back and forth on adjacent microtubule fibres in coordination, and in turn, rhythmically bend and straighten the sperm tail. This resembles how paddles are moved in synchrony to move a galley forward. On the galley the rowers are coordinated by a supervisor, but what about the dyneins?

A chemical decoration on proteins called glycylation is likely the trick. We know this type of protein modification happens on microtubules. Interestingly, glycylated microtubules have been only found in sperm tails and similar structures. This suggests that the glycylation may give a unique function to microtubules in sperm tails, which is potentially associated with the tails' dynamic movements. However, this chemical modification has been poorly investigated and its biological meaning remains unclear.

To explore the role of microtubule glycylation in sperm tail dynamics, we used genetically engineered mice. Using mice as a model animal is beneficial because they share a very similar genetic background and physiology with humans. In other words, what happens in mice most probably occurs in humans too. We edited the DNA of mice to remove the genes that are essential for glycylation. Comparing these mice lacking glycylation with normal mice, we can understand the biological function of this chemical modification.

To our surprise, the lack of glycylation did not lead to any distinct defects in mouse behaviour and general health. However, when it comes to fertilisation, the male mice showed a reduced fertilisation capacity and an abnormal sperm swim style. Notably, the lack of glycylation altered the beat of sperm tails, which was less frequent and less symmetrical. Moreover, the sperm tails were more curved towards the sperm head. As a result, the glycylation-deficient sperm could no longer swim along a straight line and tended to swim in circles. This finding reveals that glycylation is essential for keeping the rhythmic beats of sperm tails, and important for the sperm not to get lost during the travel.

To take a deeper look, we next explored how internal architectures of a sperm tail look at the molecular scale in amazing detail using a cutting-edge microscopy named cryo electron microscopy. While the overall molecular architectures of the sperm tail were unaffected in the absence of glycylation, we found that dyneins were particularly disorganised. This suggests that glycylation on microtubules serves as the 'galley supervisor' that assures the coordinated movement of the dyneins. It also explains why the sperm turned to circularly swim when glycylation was absent.

In summary, we demonstrated that glycylation – a tiny chemical decoration on proteins – arranges dyneins along microtubules, which leads to the rhythmic movement of sperm tails and efficient fertilisation in mice. As we expect this happens in humans as well, our results shed light on a new molecular mechanism possibly causing male infertility. It's noteworthy that various cells have appendages called cilia that are structurally related to sperm tails. Dysfunctional cilia with the lack of motility cause diseases called ciliopathies, which widely affect different organs. Since microtubule glycylation is also present in cilia, future studies will extend our understanding of the potential roles of glycylation in health and disease.


The Long, Winding Tale of Sperm Science

Scott Pitnick’s tattoo isn't exactly subtle. The massive black-and-white sperm twists and spires up his right forearm, appearing to burrow in and out of his skin before emerging into a fist-sized head on his bicep. Nor is the Syracuse University biologist reserved about his unusual body art, which once made an appearance in a montage of notable scientist tattoos published in The Guardian.
 
For Pitnick, his intricate ink reflects his deep fascination in sperm’s “unbelievably unique biology.” Consider, he says, that sperm are the only cells in the body destined to be cast forth into a foreign environment—a feat that requires dramatic physical changes as they travel from the testes into a woman’s reproductive tract.

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“No other cells do that,” says Pitnick, who has been studying sperm for more than 20 years. “They have this autonomy.”

In his lab, Pitnick engineers the heads of fruit fly sperm to glow a ghostly red and green so that he can observe them moving through dissected female fly reproductive tracts. He hopes his work will help reveal how sperm behave within female bodies, an area of research that's still in its relative infancy. These kinds of innovations could one day explain the great diversity of sperm shape and size across the animal kingdom. Moreover, they could ultimately help researchers develop human infertility treatments, as well as more effective male contraceptives.

“We understand almost nothing about sperm function, what sperm do,” Pitnick says. Many of the answers to these unknowns likely hide within the other half of sperm’s puzzle: female bodies. 

This might come as a disappointment to the courageous biologists who first looked upon sperm cells in their full glory in the㺑th and 18th century, using the then-revolutionary microscope. These early sperm scientists found themselves tasked with answering the most basic of questions, for instance: Are sperm living animals? Are they parasites? And, Does each sperm contain a tiny pre-formed adult human curled up inside? (We’ll get to that one later.)

Leeuwenhoek's early microscopic observations of rabbit sperm (figs. 1-4) and dog sperm (figs. 5-8). (Wikimedia Commons)

The person with the dubious honor of being the first to study sperm in detail was Anton van Leeuwenhoek, a Dutchman who developed the early compound microscope. Van Leeuwenhoek first used his new tool to examine more chaste subjects such as bee stingers, human lice and lake water in the mid-1670s. 

Colleagues urged him to turn his lens to semen. But he worried it would be indecent to write about semen and intercourse, and so he stalled. Finally, in 1677, he gave in. Examining his own ejaculate, he was immediately struck by the tiny “animalcules” he found wriggling inside.

Hesitant to even share his findings with colleagues—let alone get a wriggler tattooed on his arm—van Leeuwenhoek hesitantly wrote to the Royal Society of London about his discovery in 1677. “If your Lordship should consider that these observations may disgust or scandalise the learned, I earnestly beg your Lordship to regard them as private and to publish or destroy them as your Lordship sees fit.”

His Lordship (aka the president of the Royal Society) did opt to publish van Leeuwenhoek’s findings in the journal Philosophical Transactions in 1678—thus begetting the brand new field of sperm biology. 

It’s hard to overstate how mysterious these squirming, microscopic commas would have appeared to scientists at the time. Before the discovery of these “animalcules,” theories of how humans made more humans ranged widely, says Bob Montgomerie, a biologist who studies animal reproduction at Queen’s University in Canada. For example, some believed that vapor emitted by male ejaculate somehow stimulated females to make babies, while others believed that men actually made babies and transferred them to females for incubation. 

“You can imagine how difficult it is when you have no idea what is going on,” says Montgomerie. That is: without being able to see sperm and eggs, these scientists were really just pulling theories out of thin air.

In the 17th century, many researchers believed each spermatozoa contained a tiny, completely pre-formed human within it, as illustrated in this 1695 sketch by Nicolaas Hartsoeker. (Wikimedia Commons)

Even after van Leeuwenhoek discovered sperm in 1677, roughly 200 years passed before scientists agreed on how humans formed. Two primary fields of thought emerged along the way: On the one hand, the “preformationists” believed that each spermatozoa—or each egg, depending on who you asked—contained a tiny, completely pre-formed human. Under this theory, the egg—or sperm—simply provided a place for development to occur.

On the other hand, “epigenesists” argued that both males and females contributed material to form a new organism, though they weren’t sure who contributed exactly what. Discoveries throughout the 1700s offered more evidence for this argument, including the 1759 discovery that chicks develop organs incrementally. (Montgomerie notes this in the book Sperm Biology: An Evolutionary Perspective, which was edited by colleagues including Pitnick.)

With improvements to the microscope, mid-19th century researchers observed embryonic development within sea urchin eggs, which are conveniently transparent. These observations continued to disprove the concept of preformation, and allowed researchers to begin asking how sperm and egg work together to create new organisms.

Sperm research also shed light on other body systems. In the 1960s, researchers identified the protein dynein, which is responsible for sperm movement. “It turns out that the same motor protein is responsible for all kinds of processes that go on in cells,” says Charles Lindemann, a professor emeritus at Oakland University in Michigan who studied sperm motility. Today we know that dynein is involved in the movement of microscopic cellular structures like cilia and flagella, which are key to many bodily functions.

Still, early progress in fertility research was slow to take off. There simply weren’t very many working scientists back then at all, let alone sperm scientists, says Montgomerie. He estimates that there were only several dozen people researching sperm at that time by comparison, roughly 400,000 scientists study cancer today. “There were some people doing it, but maybe not enough,” says Montgomerie.

Pitnick adds that the few early researchers who did study sperm may not have fully appreciated the role of the female reproductive system in the fertility equation—an oversight that could explain why this area is still such a mystery today. “Part of that is a male bias in biology to think the female is not an important part of the story, and that goes way back in sperm biology to this whole idea of preformation,” says Pitnick.

On the more technical side, observing sperm move within the female is logistically very challenging. As Pitnick points out, it’s pretty hard to get a camera inside a female reproductive tract.

That's the genius behind his glowing fruit fly sperm and the ability to monitor them in real time. The video above shows the removed reproductive tract of a female fruit fly, which Pitnick has kept intact in a saline solution. When it was living, that female was mated to a green-sperm male, and then re-mated a few days later with a red-sperm male. Only the heads of the sperm are tagged with the fluorescent protein, so the tails of the sperm cannot be seen. 

With this kind of technology, Pitnick can gain insight into why so much variety exists in the shape and size of sperm. For example, the glowing sperm he studies have mega-long tails reaching up to 6 centimeters in length when unwound—roughly the length of your pinky finger, and the longest known in the animal kingdom. He has spent decades trying to understand why a fly would evolve this way, and has finally honed in on the female reproductive tract as the source for his answer.

While Pitnick focuses on flies, sperm have also captured the attention of modern scientists trying to help human couples trying to conceive. Pitnick’s findings could inadvertently help with this task. “In many cases, it is a compatibility difference between a specific male and female, and they don’t know the underlying mechanism,” he says. “Understanding sperm-female interactions can certainly shed light on understanding new explanations for infertility, and possibly new solutions for it.”

Basic sperm research will also help expedite progress in developing male contraceptives, says Daniel Johnston, chief of the Contraception Research Branch at the National Institutes of Health. So far, researchers have tried everything from gels to pills, but an effective, reliable male birth control remains elusive. Johnston says scientists still face the most basic of questions: what is sperm, anyways? 

Sperm cells vary incredibly across the animal kingdom. This single fruit fly sperm cell can reach several centimeters long when unfurled. (Romano Dalla)

“We need to really understand what makes up a sperm,” says Johnston, who has worked to describe the full protein contents of sperm—an important first step in understanding how to design effective contraceptives. “When you understand that, you can potentially start understanding what we need to inhibit.”

Recently, a private group called the Male Contraceptive Initiative launched a competition that will fund one innovative contraceptive research project.* Gunda Georg, a medicinal chemist at the University of Minnesota, has made it through the first round of the contest for her research on infertility-associated genes in mice that could ultimately be used to develop a male birth control pill.

Her current research helps determine appropriate dosage levels for such pharmaceuticals and assess potential side effects. After all, “if a man stops taking the pill, he has to completely return to normal,” Georg says.

Johnston is pleased to have the opportunity to support this type of research at the NIH, both out of interest in moving male contraceptives forward but also out of a fundamental intrigue in sperm that hasn’t let up over his 25-year career. “Sperm are fascinating," says Johnston. "There is nothing like them.”

Pitnick, naturally, agrees. The bashfulness that scientists like van Leeuwenhoek demonstrated in the early days, he says, has subsided in the field. “I don’t think there are too many biologists today that have any kind of discomfort level talking about this stuff,” says Pitnick. And for him, personally? “I love this biology,” he says. “I’ll talk to anyone about it who is willing to listen.”

Editor's Note, June 7, 2017: This piece originally stated that the Male Contraceptive Initiative was housed under the NIH it is a private endeavor.

About Laura Poppick

Laura is a freelance writer based in Portland, Maine and a regular contributor to the Science section.


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