Possible cause of male infertility
Bonn researchers decode gene that blocks sperm maturation in mice when altered
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POSSIBLE CAUSE OF MALE INFERTILITY:
GINA ESTHER MERGES AND PROF. HUBERT SCHORLE STUDY GENES INVOLVED IN SPERM MATURATION.
view moreCREDIT: UNIVERSITY HOSPITAL BONN (UKB) / ROLF MÜLLER
Bonn, 27. October - Mature spermatozoa are characterized by an head, midpiece and a long tail for locomotion. Now, researchers from the University Hospital Bonn (UKB) and the Transdisciplinary Research Unit "Life & Health" at the University of Bonn have found that a loss of the structural protein ACTL7B blocks spermatogenesis in male mice. The cells can no longer develop their characteristic shape and remain in a rather round form. The animals are infertile. The results of the study have now been published in the scientific journal "Development".
Male sperm cells are constantly produced in large quantities in the testicles during so-called spermatogenesis. In this process, the typical elongated sperm cells are formed from round germ cells. This enormous change in shape requires the fine tuned reorganization of specialized structural proteins. One of these structural proteins is ACTL7B. "Since it is exclusively made in humans and mice during the maturation of male sperm, it has been postulated that the protein is important for this phase of development," notes corresponding author Prof. Hubert Schorle from the Institute of Pathology at UKB, who is also a member of the Transdisciplinary Research Area (TRA) "Life & Health" at the University of Bonn.
To investigate the role of the structural protein in spermiogenesis, Prof. Schorle's team generated a mouse model with a mutation in the Actl7b gene using gene-editing technology. This results in a complete loss of function of ACTL7B. "Without ACTL7B, development is blocked, the cells often remain in a roundish shape, usually do not form the elongated, typical sperm shape and die to a large extent ," says first author Gina Esther Merges, a doctoral student in Professor Schorle’s laboratory.
Disruption in the network of proteins
In this context, the Bonn researchers found that ACTL7B is required for the reorganization of the cytoskeleton of spermatids. Using mass spectrometric analyses, they identified two interaction partners of ACTL7B, DYNLL1 and DYNLL2. "We were able to show that without the structural protein, DYNLL1 and 2 are not correctly localized in the round spermatids. Since it is probably a larger protein complex with further interaction partners, we attribute the above described effect to a loss of temporally and spatially precisely regulated and targeted redistribution of these proteins," Prof. Schorle notes.
This explains why the sperm of male mice with a mutated Actl7b gene is not able to develop the characteristic shape. Due to this, the animals are infertile. In addition, according to other research, there is evidence that levels of the protein ACTL7B are reduced in some fertility patients. "Our study shows that mutations in the Actl7b gene could be the cause of male infertility," says Prof. Schorle.
Publication:
Gina E. Merges, Lena Arévalo, Keerthika Lohanadan, Dirk G. de Rooij, Melanie Jokwitz, Walter Witke and Hubert Schorle; Development (2023) 150, dev201593;
DOI: https://doi.org/10.1242/dev.201593
Press contact:
Dr. Inka Väth
Deputy Press Officer at the University Hospital Bonn (UKB)
Communications and Media Office at Bonn University Hospital
Phone: (+49) 228 287-10596
About the University Hospital Bonn: The UKB cares for about 500,000 patients per year, employs about 9,000 people and has a balance sheet total of 1.6 billion euros. In addition to the more than 3,300 medical and dental students, another 585 people are trained in numerous health professions each year. The UKB is ranked first among university hospitals in North Rhine-Westphalia in the science ranking and in the Focus clinic list and has the third-highest case mix index (severity of cases) in Germany. The F.A.Z. Institute has named UKB the most sought-after employer and training champion among public hospitals in Germany in 2022 and 2023.
JOURNAL
Development
ARTICLE TITLE
Actl7b deficiency leads to mislocalization of LC8 type dynein light chains and disruption of murine spermatogenesis
ARTICLE PUBLICATION DATE
27-Oct-2023
Membrane transporter ensures mobility of sperm cells
Newly discovered mechanism contributes to a better understanding of molecular foundations of fertility
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STRUCTURE OF THE NEWLY DECODED PROTEIN FOUND IN THE MEMBRANE OF SPERM CELLS. COLOURS MARK THE DIFFERENT UNITS OF THE PROTEIN, WHICH CAN BE PUT TOGETHER TO MAKE A FUNCTIONING PROTEIN LIKE THE BUILDING BLOCKS OF A LEGO TOY.
view moreCREDIT: MARTIN F. PETER
Special proteins – known as membrane transporters – are of key importance for the mobility of sperm cells. A research team from the Heidelberg University Biochemistry Center (BZH) headed by Prof. Dr Cristina Paulino has, with the aid of cryo-electron microscopy, for the first time succeeded in decoding the structure of such a transporter and its mechanism. According to the researchers, these findings will enable a better understanding of the molecular foundations of reproductive capacity and could, in the long term, contribute to developing new approaches to treating fertility disorders and new methods of specific contraception.
Sperm cells differ fundamentally in structure and function from other cell types. After all, their only task is to track down and fuse with the egg. Sperm cells only achieve their full activity in what is called capacitation, which means the maturing of the cells in the semen. One of the final steps of this biochemical process involves increasing the sperm’s mobility. If the cells are not able to move autonomously, or only to a limited extent, the result is generally reduced fertility or a complete lack of reproductive capacity. The sperm cells cannot reach and fertilise the egg cell.
Within this final maturation process, special proteins found in the sperm membrane have a particular role. Known as membrane transporters, they are responsible for transporting nutrients, for instance, into or out of the cell. “Transporting certain ions into the cell leads to a rise in sperm mobility. For that reason, the proteins responsible for the transport are directly linked to the fertility of a sperm and thereby with the male capacity for reproduction,” Prof. Paulino underlines. Her research group at the BZH is working on the membrane transporters of sea urchins, a model system for investigating sperm.
With the assistance of cryo-electron microscopy, the scientists have now been able to decode the structure of an important sperm membrane transporter at the molecular level. Amongst other things, they discovered what its functional units look like, and how they interconnect and interact. “We have observed that the key protein is, like a lego toy, constructed from different building units. These building blocks are basically known from other proteins, but have never been observed in such a combination. With the aid of this information, we were able to decode the mechanism of this transporter for the first time,” explains Dr Valeria Kalienkova from the University of Bergen (Norway), a former member in Prof. Paulino’s research group.
According to Dr Martin Peter, a member of Prof. Paulino’s research team, these new findings will be helpful in the next step, developing potential substances that influence this mechanism. They may make it possible to activate or deactivate the functions of the proteins. The extent to which these findings can be transferred to the mechanisms of human sperm will call for further investigation. In the long term, they contain potential for finding new ways of treating infertility, or vice versa, of preventing the sperm from fertilising the egg cell.
The results of the research studies have appeared in the journal “Nature”. Due to the research group moving from the Netherlands to Germany, the studies were carried out both at the University of Groningen (Netherlands) and at the Heidelberg University Biochemistry Center. They were funded by the Dutch Research Council, and the Swiss National Science Foundation.
JOURNAL
Nature
SUBJECT OF RESEARCH
Cells
ARTICLE TITLE
Structures of a sperm-specific solute carrier gated by voltage and cAMP
ARTICLE PUBLICATION DATE
25-Oct-2023
Sperm's secret voltage switch: Scientists unlock the mystery of motility
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CHEMO-ATTRACTANT BINDING TO SPERM CAUSES A CHANGE IN VOLTAGE, WHICH ACTIVATES THE TRANSPORTER SLC9C1. THE STRUCTURE OF SLC9C1 IS HERE DESCRIBED FOR THE FIRST TIME. ONCE ACTIVATED THE SLC9C1 PROTEIN EXCHANGES NA+ FOR H+ IONS AND THIS MAKES THE SPERM FLAGELLUM MORE ALKALINE AND, TOGETHER WITH CAMP, LEADS TO THE OPENING OF CA2+-CHANNELS THAT RESULTS IN A DIRECTED MOVEMENT OF THE SPERM. THIS SEQUENCE OF EVENTS, PRESENT IN SPECIES AS DISTANT AS CORALS AND HUMAN, ARE ESSENTIAL FOR FERTILIZATION.
view moreCREDIT: ILLUSTRATION BY VED MEHTA/STOCKHOLM UNIVERSITY.
Researchers at Stockholm University have unveiled the hidden intricacies of how sperm go from passive bystanders to dynamic swimmers. This transformation is a pivotal step in the journey to fertilization, and it hinges on the activation of a unique ion transporter.
Imagine sperm as tiny adventurers on a quest to reach the ultimate treasure, the egg. They don't have a map, but they make use of something even more extraordinary: chemo-attractants. These are chemical signals released by the egg that act as siren call, directing and activating the sperm. When these signals bind to receptors on the sperm's surface, it triggers a series of events, starting their movement towards the egg. And in this intricate scenario, one key player is a protein known as "SLC9C1."
It's exclusively found in sperm cells, and it is usually not active. However, when the chemo-attractants interact with the sperm’s surface, everything changes.
“SLC9C1 operates like a highly sophisticated exchange system. It swaps protons from inside the cell for sodium ions from the outside, temporarily creating a less acidic environment within the sperm. This change in the internal environment triggers increased sperm motility“, says David Drew, Professor in Biochemistry at Stockholm University.
The activation of SLC9C1 is driven by a change in voltage that occurs when chemo-attractants attach to the sperm. To accomplish this, SLC9C1 uses a unique feature called a voltage-sensing domain (VSD). Typically, VSD domains are associated with voltage-gated ion channels. But in the case of SLC9C1, it's something truly exceptional in the realm of transporters.
Researchers, led by David Drew, have unveiled the secrets behind SLC9C1's inner workings and provides the first example of voltage-sensing domain activation of a transporter and its connection via an unusually long voltage-sensing (S4) helix.
“The VSD domain responds to the change in voltage by pushing its rodlike S4 helix inwards. This clears the way for ion exchange by SLC9C1, ultimately initiating sperm motility”, says David Drew.
“Transporters work very differently than channels and, as such, the VSD is coupled to the sperm protein in a way that we have just never seen before, or even imagined. Its exciting to see how nature has done this and perhaps, in the future, we can learn from this to make synthetic proteins that can be turned-on by voltage or develop novel male contraceptives that work by blocking this protein”, David Drew notes.
The research was made possible through funding from the European Research Council (ERC) grant EXCHANGE.
Contact info: David Drew, Professor in Biochemistry, Stockholm University
Email: david.drew@dbb.su.se
Phone: +46 72-14 627 44
JOURNAL
Nature
METHOD OF RESEARCH
Experimental study
SUBJECT OF RESEARCH
Cells
ARTICLE TITLE
'Structure and electromechanical coupling of a voltage-gated Na+/H+ exchanger'
ARTICLE PUBLICATION DATE
25-Oct-2023
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