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Category: Cell biology, development and evolution

Dwarfism: a new development to restore bone growth

Posted on by Priscille Rivière

Achondroplasia is the most common form of dwarfism, affecting roughly one child in every 15,000 births[1]. Inserm researcher Elvire Gouze, and her associates from the Mediterranean Centre for Molecular Medicine in Nice (Inserm Unit 106), have succeeded in restoring bone growth in mice suffering from this developmental pathology. The proof-of-concept created by the researchers is for a therapy based on injecting a particularly promising human growth factor, which restores the growth process in long bones. Its results include a reduced mortality rate in the treated mice, with no complications associated with the disease. No apparent toxicity was observed over the short term.

The results of this research were published in the  Science Translational Medicine review on 18 September.

Elvire Gouze

Sophie Garcia and Elvire Gouze in Inserm Unit 1065 “Centre méditerranéen de médecine moléculaire” in Nice

Achondroplasia is a rare genetic disease characterized by abnormal bone development. The related growth failure affects bones in the upper and lower limbs, and some bones in the skull; people suffering from it are short, reaching no more than an average of 135 cm in adulthood. In the most severe cases, deformation of the skull and vertebrae may result in neurological and/or orthopaedic complications. This pathology is caused by mutations in the FGFR3 (Fibroblast growth factor 3) gene.  The protein produced by this gene is a receptor known for its role in bone growth regulation. Normally, growth can only occur through a subtle mechanism during which the FGF growth factor bonds with the FGFR3 receptor and then separates from it. In the case of achondroplasia, the receptor/growth factor pair is disturbed and prevents the bone from growing in a constant manner.

A new strategy to restore bone growth

In this study, researchers from Inserm and the Université de Nice Sophia Antipolis have found a way to prevent constant protein activation. They implemented a new strategy, which consists of using a decoy – functional soluble human FGFR3 receptors – that is injected in mice afflicted with the disease, thus restoring the equilibrium required between bone growth activation and inhibition.

The solution containing soluble FGFR3 receptors was injected into growing mice suffering from dwarfism twice a week over a three-week period.  The additional normal receptors made it possible for the growth factor to bond and separate normally, thus restoring bone growth. Mutated mice then grew normally and reached the average adult size. Once the therapy had stopped, the researchers then monitored the mice over an eight month period to check there were no signs of therapy toxicity. During this monitoring, the researchers observed that an increased pelvis size enables reproduction with litters identical to disease-free mice.

“Rather surprisingly, our strategy prevents the most severe complications observed in mice (reduced mortality rate, respiratory problems, etc.). This could lead us to believe that injection-based therapy could replace surgery for children suffering from this disease” explains Elvire Gouze, Inserm researcher.

Preventing the development of achondroplasia

Today, there are no proven therapies to prevent the development of the disease, even if some (such as growth hormone injections or surgical limb-lengthening) have undergone trials without any convincing results.

“The product that we tested has major advantages compared with those tested in other ongoing trials: its lifetime in the body is sufficiently long, meaning daily injections are not necessary. We think that our approach could be effective when treating children with achondroplasia and possibly other forms of dwarfism” underlines the researcher, who is the main author of the study.

The researchers will now endeavour to verify that there are no long-term toxic effects. Before undertaking clinical studies in human patients, they must also identify the minimum dose at which the therapy is effective and when it becomes toxic. Another area to be explored is to determine whether it is possible to begin the therapy later, thereby increasing the number of patients who could benefit from this treatment.

[1] Source: Orphanet Achondroplasie

A new therapeutic strategy to combat prion and Alzheimer’s diseases

Posted on by Priscille Rivière

A work performed by the teams headed by Benoit Schneider and Odile Kellermann (INSERM Unit 747, team “Stem cells, Signalling and Prions”, Université Paris Descartes) as well as Jean-Marie Launay’s team (INSERM Unit 942 Hôpital Lariboisière and the FondaMental Foundation) was published this week in the magazine Nature Medicine. The article revealed that in neurons, an enzyme, the kinase PDK1, is involved in the accumulation of the pathological proteins involved in prion and Alzheimer’s diseases. The researchers show that the pharmacological inhibition of this enzyme exerts a beneficial effect towards both pathologies.

Details of this research were published in the magazine Nature Medicine

Différenciation cellulaire

Mouses Neurones – 7 days – © Inserm/L.Peris

Prion diseases (Creutzfeld-Jakob disease in humans) and Alzheimer’s disease are associated with an accumulation of abnormal proteins in the brain. These are the scrapie prion protein (PrPSc) in the case of prion diseases and Aß amyloid peptides in the case of Alzheimer’s. In the brain, PrPSc and Aß peptides exert their toxic effect by causing the death of neurons, at the root of the clinical symptoms associated with these diseases.

It is acknowledged that the production of the pathological proteins PrPSc and Aß40/42 originate from a defect in the physiological cleavage of the entire, non-pathological prion protein (PrPC) or of the amyloid peptides precursor (APP). However, it remained unsolved why this cleavage, which normally protects neurons, is altered in prion and Alzheimer’s diseases.

The work performed by Benoit Schneider (CNRS researcher in INSERM Unit 747, “Stem cells, Signalling and Prions”, Université Paris Descartes) and Jean-Marie Launay (INSERM Unit 942 Hôpital Lariboisière) in collaboration with other French teams working in the prion field has just identified a cascade of reactions that blocks the beneficial cleavage of PrPC and APP by the alpha-secretase TACE (an acronym for the TNFα Converting Enzyme). The researchers demonstrate how TACE dysregulation contributes to neurodegeneration by causing the accumulation of the PrPSc and Aß40/42 pathological proteins and exacerbating neuron sensitivity to inflammation.

Under normal physiological conditions, TACE is present on the surface of neurons, where it cleaves PrPC, APP and the receptors to TNFα inflammatory factor (TNFR), thus restricting the production of the pathological proteins PrPSc and Aß and protecting neurons from the toxic effects of TNFα.

schéma Prions Alzheimer en

© Benoit Schneider & Mathéa Pietri, August 2013

In neurons infected by pathogenic prions as in the “Alzheimer’s” neurons, the TACE protease is no longer present on the cell surface but is found inside neurons. This internalization diverts TACE away from its substrates, that is PrPC, APP and TNFR, and thereby cancels its neuroprotective activity. The researchers reveal for the first time that the kinase PDK1 plays a key role in controlling the localization of TACE in neurons. The overactivation of PDK1 is responsible for the internalization of TACE in diseased neurons (those infected by prions and Alzheimer’s neurons) as in the brains of patients suffering from Alzheimer’s disease.

The pharmacological blockade of PDK1 relocates TACE to the surface of neurons and restores its neuroprotective function. The inhibition of PDK1 protects neurons from neurodegeneration by rescuing the physiological cleavage of PrPC, APP and TNFR by TACE.

“Based on our work on prion infection, we succeded in identifying PDK1 as a new therapeutic target not only for Creutzfeld-Jakob disease but also for Alzheimer’s disease” explained the researchers.

The action of PDK1 on TACE was demonstrated in vitro using a neuronal cell line and cultures of neurons isolated from the brains of mice that had been infected by pathogenic prions, and in vivo using animal models. Treatment with PDK1 pharmacological inhibitor attenuates the motor deficits and extends the life span of mice infected with prions. Using three mouse models of Alzheimer’s pathology, the researchers showed that the treatment also counteracted memory and cognitive deficits associated with Alzheimer pathogenesis.“Because treatments available to combat prion and Alzheimer’s diseases are few and their efficacy limited, these results could open up new avenues for the treatment of these neurodegenerative diseases”, conclude the researchers.

By demonstrating that the inhibition of PDK1 alleviates both prion and Alzheimer’s diseases, these data argue that at a mechanistic level AD links to prion diseases. Dysregulation of PDK1-dependent TACE cleavage activity emerges as a central event in neurodegenerative pathways involved in both diseases.

The challenge is now to understand how pathogenic prions or amyloid Ab peptides trigger PDK1 activation.

Novel molecules to target the cytoskeleton

Posted on by Priscille Rivière

The dysfunction of the cytoskeleton, a constituent element of the cell, is often associated with pathologies such as the onset of metastases. For this reason, it is a target of interest in numerous therapies. Teams from CNRS, the Université de Strasbourg and Inserm, led by Daniel Riveline1, Jean-Marie Lehn2 and Marie-France Carlier3, have synthesized molecules capable of causing rapid growth of actin networks, one of the components of the cytoskeleton. This is a breakthrough because, until now, only molecules that stabilize or destroy the cytoskeleton of actin have been available. These compounds with novel properties, whose action has been elucidated both in vitro and in vivo, provide a new tool in pharmacology. This work was published in the journal Nature Communications on 29 July 2013.

The cytoskeleton is mainly composed of actin filaments and microtubules. Made of polymers in dynamic assembly and constantly constructing and deconstructing itself, it affects numerous cellular processes such as intracellular movement, division and transport. It is involved in key steps of embryogenesis and other processes essential to life. Consequently, its malfunctioning can lead to serious pathologies. For example, the onset of certain metastases is revealed by an increased activity of the cytoskeleton. Identifying new molecules that target the cytoskeleton thus represents a major challenge.

Until now, the molecules known and used in pharmacology had the effect of stabilizing or destroying the cytoskeleton of actin. Actin allows vital actions to be performed by assembling and disassembling itself spontaneously, continually and rapidly in the form of filaments that organize themselves and form networks of parallel bundles or intertwined meshes (known as lamellar networks). Derived from supramolecular chemistry[4], the new compounds synthesized by the researchers have original properties: within several minutes, they bring about the growth of lamellar networks of actin filaments. This is the first time that a pharmacological tool induces growth of the actin network — something that living organisms do all the time. In this way, the researchers have shown that the action of these compounds is specific in vivo (on cells). In addition, they have identified the growth mechanism of the actin network by comparative in vivo and in vitro studies in order to ensure the validity of the process.

For cellular or molecular biology, this tool proposes a new mode of possible action on the cytoskeleton and thus opens new research perspectives for deciphering the living world. This finding could lead to the development of new compounds, derived from the same chemistry, and potential candidates for new therapies targeting the cytoskeleton.

[1] Institut de Science et d’Ingénierie Supramoléculaires (CNRS/Université de Strasbourg) and Institut de Génétique et de Biologie Moléculaire et Cellulaire (CNRS/Université de Strasbourg/Inserm).

[2] Institut de Science et d’Ingénierie Supramoléculaires (CNRS/Université de Strasbourg).

[3] Laboratoire d’Enzymologie et Biochimie Structurales of CNRS.

[4] Supramolecular chemistry, the science of self-assembly and self-organization at the molecular scale, focuses on chemical entities resulting from the interactions between molecular objects.

How is the male genome preserved until it reaches the egg?

Posted on by Priscille Rivière

When the male genome carried in the spermatozoid leaves the male body to reach the egg, it undergoes numerous transformations. A team led by Saadi Khochbin in Mixed Research Unit 823 at the Institut Albert Bonniot Research Centre (Inserm/Joseph Fourier University) in Grenoble has described the molecular mechanisms that enable the transmission of the male genome to the egg. The researchers have revealed the essential role played by a tiny structure  which compact and preserve the genome in the spermatozoid during its journey to the egg. These results were published on July 24th in the journal Genes & Development.

Spermatozoide-khochbin

Spermatozoid – © Inserm / Denise Escalier

One of the challenges of reproduction is to discover how male DNA is carried via the spermatozoids, the highly specialised germinal cells. These are capable of leaving the organism and surviving during their journey from the male to the female body, at which time it is necessary to ensure that the genome it contains is safe in order to preserve it for fertilisation. When spermatozoids leave the male organism and start their journey to the female body, the genome is necessarily secured and preserved until the fertilization. The genome gradually changes its spatial configuration during spermatogenesis. This enables the DNA to be transported in a very compact, and thus very resistant, form. A defect in the compacting process can result in infertility.

Hitherto, although scientists had identified the molecules that contribute to the compaction of the DNA – histones, transition proteins, protamines, the molecular determinants causing these rapid changes in configuration remain obscure.

The “Epigenetics and cell signalling” Inserm Team headed by Saadi Khochbin, CNRS Research Director, described for the first time how the “organising” element in the male germinal cells directs the very accurate and specific compacting of the male genome. It is a special histone called TH2B, which was discovered in 1975, one of the earliest histones to be identified. This tiny protein attaches itself to the DNA during spermatogenesis and gives it the special configuration required for its final compaction. This is how the paternal genome, transported by the spermatozoid, leaves the male body and reaches the egg. The researchers also discovered that, unexpectedly, this histone is also present in the egg and participates in the repackaging of the male genome after fertilisation as soon as it enters the egg.

“We therefore discovered an important element in the transmission of the paternal genetic information that also participates in its packaging for despatch from the male reproductive organ as well as in its receipt by the female cell”, explains Saadi Khochbin, principal author of the study.

The research required the use of several mouse models and approaches involving very sophisticated recent technology for the purpose of exploring the genome as a whole (the genomic and transcriptomic techniques) and understanding new mechanisms on the molecular scale (proteomic approaches and structural modelling).

On a basic level, the research improves knowledge of male genome transmission and the way in which the male genome is transmitted during reproduction; there are also implications in the understanding of infertility and the optimisation of medically assisted procreation.

The surprising ability of blood stem cells to respond to emergencies

Posted on by Priscille Rivière

A research team of Inserm, CNRS and MDC lead by Michael Sieweke of the Centre d’Immunologie de Marseille Luminy (CNRS, INSERM, Aix Marseille Université) and Max Delbrück Centre for Molecular Medicine, Berlin-Buch, today revealed an unexpected role for hematopoietic stem cells: they do not merely ensure the continuous renewal of our blood cells; in emergencies they are capable of producing white blood cells “on demand” that help the body deal with inflammation or infection. This property could be used to protect against infections in patients undergoing bone marrow transplants, while their immune system reconstitutes itself. The details of the research is published in Nature on april 10th 2013.

Macrophages

Cells in our blood feed, clean and defend our tissues, but their lifespan is limited. The life expectancy of a red blood cell rarely exceeds three months, our platelets die after ten days and the vast majority of our white blood cells survive only a few days.

The body must produce replacement cells in a timely manner. This is the role of hematopoietic stem cells, more commonly called blood stem cells. Nestled in the core of the bone marrow (the soft tissue in the center of long bones such as the chest, spine, pelvis and shoulder), they dump billions of new cells into the bloodstream every day. To accomplish this strategic mission, they must not only multiply but also differentiate, i.e. to produce specialized white blood cells, red blood cells or platelets.

For many years, researchers have been interested in how this process of specialization is triggered in stem cells. Michael Sieweke and his team previously discovered that the latter do not engage randomly in a particular differentiation pathway but “decide” their fate under the influence of internal factors and signals from the environment.

An important issue remains: how do stem cells manage to respond appropriately to emergencies? For example, are they able to meet the demand by producing white blood cells like macrophages to eat microbes during infection?

Until now, the answer was clear: the stem cells could not decode such messages and were content to differentiate randomly. Michael Sieweke’s team has demonstrated that, far from being insensitive to these signals, stem cell perceive them and in return manufacture the cells that are most appropriate for the danger that is faced.

“We have discovered that a biological molecule produced in large quantities by the body during infection or inflammation directly shows stem cells the path to take,” said Dr. Sandrine Sarrazin, Inserm researcher, co-author of the publication. “As a result of this molecule, called M-CSF (Macrophage Colony-Stimulating Factor), the switch of the myeloid lineage (the PU.1 gene) is activated and the stem cells quickly produce the cells that are best suited to the situation such as macrophages.”

Now that we have identified this signal, it may be possible in the future to accelerate the production of these cells in patients facing the risk of acute infection,” said Dr. Michael Sieweke, CNRS Research Director. “This is the case for 50,000 patients worldwide each year* who are totally defenseless against infections just after bone marrow transplantation. Thanks to M-CSF, it may be possible to stimulate the production of useful cells while avoiding to produce those that can inadvertently attack the body of these patients. They could therefore protect against infections while their immune system is being reconstituted”.

About the discovery

This seemingly simple discovery is quite original, both in its approach and by the technology it required. To reach their conclusions the team had to measure the change of state in each cell. This was a double challenge: the stem cells are not only very rare (there is only one stem cell per 10,000 cells in the bone marrow of a mouse), but they are also completely indistinguishable from their descendants.

“To differentiate the protagonists we used a fluorescent marker to indicate the status (on or off) of the myeloid cell switch: the protein PU.1. First in the animal, then by filming the accelerated cell differenciation under a microscope, we showed that stem cells “light-up” almost immediately in response to M-CSF,” said Noushine Mossadegh-Keller, CNRS assistant engineer, co-author of this publication. “To be absolutely sure, we recovered the cells one by one and confirmed that the myeloid genes were activated in all the cells that had turned green: once they perceived the warning message, they changed identity.”

A fish to detect contaminant endocrinal disruptors

Posted on by Priscille Rivière

The researchers from INERIS and Inserm (a team managed by Olivier Kah in Inserm unit 1085 “Institute for research into health, environment and work”) have just developed a test in fish that allows us to detect the endocrinal disrupting effects of certain contaminants in the environment. The researchers based their work on a gene that expresses in the brain, and that reacts strongly to certain endocrinal disruptors. In order to make it easier to measure this gene, they used a fluorescent reporter gene. By using the embryos of zebrafish that are transparent, we can see the effects in the brain when the embryos are exposed to disruptor pollutants. The results of these works are published in the review Plos One.

Fluorescence seen in the brain of the fish embryo, induced by the expression of gene cyp19a1b bound to the GFP.

Over the last 20 years, numerous studies have proved the harmful effects of artificial compounds on the reproductive capacity of organisms. Certain pollutants (nonylphenols, bisphenol A, pesticides, pharmaceutical residues, etc.) present in surface water, industrial waste or sediments are capable of mimicking the effects of oestrogens. They thus modify the biological processes that are controlled by oestrogens and are involved in the reproduction and growth functions of organisms, with potentially harmful consequences for the health of living creatures and their progeny. Such substances are known as “endocrinal disruptors” (ED).

Pollutants with oestrogen activity also affect the brain

The originality of the work carried out by the Inserm and INERIS researchers resides in the fact that the study of endocrinal disruptors concentrates on a gene that expresses only in the brain, and demonstrates the sensitivity of the nervous system to pollutants. The results obtained by the researchers confirm that in the fish embryo, a certain number of substances affect the activity of the stem cells in the brain, cells that are vital to the development of the central nervous system. This effect is seen in the expression of a specific gene in the brain that is extremely sensitive to oestrogens: gene cyp19a1b.

A zebrafish model to characterize ODs

Based on these observations, the INERIS and Inserm teams developed a test to detect oestrogen activity in a transgenic fish model. This transgenic zebrafish model (1) helps to identify the effect of pollutants on an enzyme from gene cyp19a1b, aromatase, that is responsible for the synthesis of oestrogens in the body.

The brain of the fish embryos uses a fluorescent reporter known as GFP (Green Fluorescent Protein), that renders it fluorescent when exposed to substances that mimic oestrogens.

21 components (e.g. natural or synthetic oestrogens; alkylphenols, bisphenols) of the 45 tested induced varying degrees of fluorescence. The metabolic capabilities of the model allowed us to detect substances such a certain androgens and certain synthetic progestatives (used in the contraceptive pill).

A test of this type is helpful in evaluating chemical substances, as required by the REACh (2) regulation. This tool is a complement to the existing in-vitro systems, and it has the advantage of integrating what will happen to pollutants in the body and of taking account of their metabolism, something than cannot always be done using tests on cells. Given its sensitivity, it could also be used to monitor aquatic environments.

The INERIS and Inserm researchers have finally opened up new prospects in the field of study of endocrinal disruptors in the central nervous system.

For the researchers themselves, it appears that this simple, robust and sensitive test will have many fields of application in assessing the risks implied in oestrogenic endocrinal disruptors.

Financed by the Ministry in charge of Ecology and the National Research Agency, the research undertaken by INERIS and Insert is aimed at pinpointing the ED potential of these chemicals, that are used in medication, cosmetics, phytosanitory products, plastics, etc.

About INERIS
The mission of the French National Institute for Environmental Technology and Hazards is to help to prevent hazards resulting from economical activities from affecting health, safety of persons and belongings, and the environment. It runs research programs aimed at better understanding the phenomena likely to lead to hazardous situations or dangers for the environment or health and developing its knowledge of prevention. Its scientific and technical know-how are made available to the state authorities, companies and local authorities so as to help them make the best decisions to improve environmental safety. Created in 1990, INERIS is a public commercial and industrial institute placed under the authority of the Ministry of the Ecology, Sustainable Development and Energy. It has a staff of 588 persons, based mainly in Verneuil-en-Halatte, in the Oise ‘département’. Website: www.ineris.fr.

About Inserm
Founded in 1964, the French National Health and Medical Research Institute (Inserm) is a public science and technology institute, jointly supervised by the French Ministry of Higher Education and Research and the Ministry of Health. The mission of its scientists is to study all diseases, from the most common to the most rare, through their work in biological, medical and public health research. Inserm support over 30à laboratories throughout France. In total, the teams include nearly 13,000 researchers, engineers, technicians and administrative staff, etc. Inserm is a member of the French Life Sciences and Healthcare Alliance, founded in April 2009 along with the CNRS (The French National Research Centre), CEA (Atomic Energy and Alternative Energy Commission), Inra (The National Institute for Agricultural Research), Inria (The French National Institute for Research in Computer Science and Control), IRD (The Institute for Research into Development), The Institut Pasteur, the Conference of University Presidents (CPU) and the Conference of Regional and University Hospital CEOs. This alliance forms part of the policy to reform the research system by better coordinating the parts played by those involved and by strengthening the position of French research in this field through a concerted plan.

Footnotes:

(1) In collaboration with Professor B.C. Chung of the Academia Sinica in Taiwan.

(2) Registration, Evaluation, Authorisation and Restriction of Chemical substances: European Parliament rule and directive No. 1907/2006 of December 18, 2006, concerning the registration, evaluation and authorization of chemical substances and the restrictions applicable to these substances.

(French) Progéria – Découverte du mécanisme moléculaire qui préserve les cellules neurales du vieillissement accéléré

Posted on by Priscille Rivière

Sorry, this press release is only available in French.

(French) Découverte d’une nouvelle règle d’organisation spatiale des chromosomes qui reflète leur fonctionnement

Posted on by Priscille Rivière

Sorry, this press release is only available in French.

New discovery of proteins involved in positioning muscular nuclei

Posted on by Priscille Rivière

The position of cellular nuclei in muscle fibres has an important role in some muscle weaknesses. Edgar Gomes, an Inserm researcher in the myology group at the Institute of Myology (mixed Inserm/UPMC unit) recently made this discovery in collaboration with an American team. The researchers identified several proteins involved in “correctly” positioning nuclei, which is required for the muscles to function. Their results are published in a letter in the Nature review, dated 18 March.

In order to move, living beings need muscles, and, more specifically, skeletal muscles that are controlled by the nervous system. Skeletal muscles are composed of cylindrical muscle fibres with a multitude of peripheral nuclei. Until now, little was known about the mechanism used to position nuclei on the edge of muscle fibres. A team of French-American researchers has tried to better understand the reasons behind nuclei layout.

Edgar Gomes and his team of collaborators have identified the mechanism involved in positioning nuclei in muscle fibres. The researchers identified (in Drosophila and mice) two proteins involved in positioning the nuclei: protein Kif5B, which belongs to the kinesin family (molecular motor), and protein MAP7, which is used to move different organelles (1) in cells.

This result was achieved by mutating MAP7 and Kif5b protein-coding genes in the Drosophila and by studying the development of the embryo. In this case, they observed that the nuclei were not correctly aligned in the muscle fibres.

“MAP7 is required to position nuclei in muscle fibre in Drosophila and in mammals” states Edgar Gomes, Inserm researcher. The research team succeeded in describing the nuclei-positioning mechanism in fibres, which involved the MAP7 protein and its interaction with the molecular motor: kinsin Kif5b. They demonstrated that a mutation of these proteins did not affect muscle extension or its attachment to the skeleton: only the position of the nuclei was affected.

By making both proteins interact together, Edgar Gomes’ team suggest that MAP7 binds with Kif5b to encourage nuclei positioning. “Furthermore, these proteins act together, both physically and genetically, and their physical bond is required for correct nuclei positioning. Our results show that they are required for the muscle to function correctly” underlines Edgar Gomes.

Muscular diseases lead to weaknesses in the fibres and can be associated with a cellular nuclei alignment failure. Edgar Gomes and his team have demonstrated that by correctly replacing the nuclei, the muscle recovers its functions. “We suggest that by correcting muscular positioning faults in patients suffering from myopathies, these patients may see improvements in their muscular functioning” concludes Edgar Gomes.

Footnote

(1) Specialized structures in the cell contained in the cytoplasm

Comment sont sélectionnés les spermatozoïdes lors de la fécondation?

Posted on by Priscille Rivière

cp_arnoult_spermato27avr10

fig.-a-b-c-spermatozoïdes 27avr10

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