Publications by authors named "Byambajav Buyandelger"

16 Publications

  • Page 1 of 1

A human cell type similar to murine central nervous system perivascular fibroblasts.

Exp Cell Res 2021 May 31;402(2):112576. Epub 2021 Mar 31.

Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden. Electronic address:

The brain vasculature has several specific features, one of them being the blood-brain barrier (BBB), which supports and protects the brain by allowing for the passage of oxygen and nutrients, while at the same time preventing passage of pathogens and toxins. The BBB also prevents efficient delivery of drugs to the brain, e.g. for treatment of brain tumors. In the murine brain, perivascular fibroblasts were recently identified as a novel potential constituent of the BBB. Here we present the existence of human cells that could be the equivalent to the murine brain perivascular fibroblasts. Using RNA sequencing, we show a similar transcriptomic profile of cultured human brain cells and murine perivascular fibroblasts. These data open up a window for new hypotheses on cell types involved in human CNS diseases.
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http://dx.doi.org/10.1016/j.yexcr.2021.112576DOI Listing
May 2021

Single-cell analysis uncovers fibroblast heterogeneity and criteria for fibroblast and mural cell identification and discrimination.

Nat Commun 2020 08 7;11(1):3953. Epub 2020 Aug 7.

Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre, Blickagången 6, SE-14157, Huddinge, Sweden.

Many important cell types in adult vertebrates have a mesenchymal origin, including fibroblasts and vascular mural cells. Although their biological importance is undisputed, the level of mesenchymal cell heterogeneity within and between organs, while appreciated, has not been analyzed in detail. Here, we compare single-cell transcriptional profiles of fibroblasts and vascular mural cells across four murine muscular organs: heart, skeletal muscle, intestine and bladder. We reveal gene expression signatures that demarcate fibroblasts from mural cells and provide molecular signatures for cell subtype identification. We observe striking inter- and intra-organ heterogeneity amongst the fibroblasts, primarily reflecting differences in the expression of extracellular matrix components. Fibroblast subtypes localize to discrete anatomical positions offering novel predictions about physiological function(s) and regulatory signaling circuits. Our data shed new light on the diversity of poorly defined classes of cells and provide a foundation for improved understanding of their roles in physiological and pathological processes.
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http://dx.doi.org/10.1038/s41467-020-17740-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414220PMC
August 2020

Genetic epidemiology of titin-truncating variants in the etiology of dilated cardiomyopathy.

Biophys Rev 2017 Jun 5;9(3):207-223. Epub 2017 May 5.

Integrated Cardio Metabolic Centre (ICMC), Karolinska Institutet, 141 57, Huddinge, Sweden.

Heart failure (HF) is a complex clinical syndrome defined by the inability of the heart to pump enough blood to meet the body's metabolic demands. Major causes of HF are cardiomyopathies (diseases of the myocardium associated with mechanical and/or electrical dysfunction), among which the most common form is dilated cardiomyopathy (DCM). DCM is defined by ventricular chamber enlargement and systolic dysfunction with normal left ventricular wall thickness, which leads to progressive HF. Over 60 genes are linked to the etiology of DCM. Titin (TTN) is the largest known protein in biology, spanning half the cardiac sarcomere and, as such, is a basic structural and functional unit of striated muscles. It is essential for heart development as well as mechanical and regulatory functions of the sarcomere. Next-generation sequencing (NGS) in clinical DCM cohorts implicated truncating variants in titin (TTNtv) as major disease alleles, accounting for more than 25% of familial DCM cases, but these variants have also been identified in 2-3% of the general population, where these TTNtv blur diagnostic and clinical utility. Taking into account the published TTNtv and their association to DCM, it becomes clear that TTNtv harm the heart with position-dependent occurrence, being more harmful when present in the A-band TTN, presumably with dominant negative/gain-of-function mechanisms. However, these insights are challenged by the depiction of position-independent toxicity of TTNtv acting via haploinsufficient alleles, which are sufficient to induce cardiac pathology upon stress. In the current review, we provide an overview of TTN and discuss studies investigating various TTN mutations. We also present an overview of different mechanisms postulated or experimentally validated in the pathogenicity of TTNtv. DCM-causing genes are also discussed with respect to non-truncating mutations in the etiology of DCM. One way of understanding pathogenic variants is probably to understand the context in which they may or may not affect protein-protein interactions, changes in cell signaling, and substrate specificity. In this regard, we also provide a brief overview of TTN interactions in situ. Quantitative models in the risk assessment of TTNtv are also discussed. In summary, we highlight the importance of gene-environment interactions in the etiology of DCM and further mechanistic studies used to delineate the pathways which could be targeted in the management of DCM.
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http://dx.doi.org/10.1007/s12551-017-0265-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498329PMC
June 2017

Molecular disturbance underlies to arrhythmogenic cardiomyopathy induced by transgene content, age and exercise in a truncated PKP2 mouse model.

Hum Mol Genet 2016 09 12;25(17):3676-3688. Epub 2016 Jul 12.

Cardiovascular Genetic Centre, Institute of Biomedical Research of Girona (IDIBGI), Girona, Spain,

Arrhythmogenic cardiomyopathy (ACM) is a disorder characterized by a progressive ventricular myocardial replacement by fat and fibrosis, which lead to ventricular arrhythmias and sudden cardiac death. Mutations in the desmosomal gene Plakophilin-2 (PKP2) accounts for >40% of all known mutations, generally causing a truncated protein. In a PKP2-truncated mouse model, we hypothesize that content of transgene, endurance training and aging will be determinant in disease progression. In addition, we investigated the molecular defects associated with the phenotype in this model. We developed a transgenic mouse model containing a truncated PKP2 (PKP2-Ser329) and generated three transgenic lines expressing increasing transgene content. The pathophysiological features of ACM in this model were assessed. While we did not observe fibro-fatty replacement, ultrastructural defects were exhibited. Moreover, we observed transgene content-dependent development of structural (ventricle dilatation and dysfunction) and electrophysiological anomalies in mice (PR interval and QRS prolongation and arrhythmia induction). In concordance with pathological defects, we detected a content reduction and remodeling of the structural proteins Desmocollin-2, Plakoglobin, native Plakophilin-2, Desmin and β-Catenin as well as the electrical coupling proteins Connexin 43 and cardiac sodium channel (Na1.5). Surprisingly, we observed structural but not electrophysiological abnormalities only in trained and old mice. We demonstrated that truncated PKP2 provokes ACM in the absence of fibro-fatty replacement in the mouse. Transgene dose is essential to reveal the pathology, whereas aging and endurance training trigger limited phenotype. Molecular abnormalities underlay the structural and electrophysiological defects.
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http://dx.doi.org/10.1093/hmg/ddw213DOI Listing
September 2016

Desmin, desminopathy and the complexity of genetics.

J Mol Cell Cardiol 2016 Mar 22;92:93-5. Epub 2016 Jan 22.

AstraZeneca R&D Mölndal, R&D, Innovative Medicines & Early Development, Cardiovascular & Metabolic Diseases iMed, Pepparedsleden 1, 431 83 Mölndal, Sweden; ICMC (Integrated Cardio Metabolic Centre), Karolinska Institutet, Myocardial Genetics, Karolinska University Hospital in Huddinge (M54), 141 86, Huddinge, Sweden. Electronic address:

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http://dx.doi.org/10.1016/j.yjmcc.2016.01.017DOI Listing
March 2016

ZBTB17 (MIZ1) Is Important for the Cardiac Stress Response and a Novel Candidate Gene for Cardiomyopathy and Heart Failure.

Circ Cardiovasc Genet 2015 Oct 14;8(5):643-52. Epub 2015 Jul 14.

Background: Mutations in sarcomeric and cytoskeletal proteins are a major cause of hereditary cardiomyopathies, but our knowledge remains incomplete as to how the genetic defects execute their effects.

Methods And Results: We used cysteine and glycine-rich protein 3, a known cardiomyopathy gene, in a yeast 2-hybrid screen and identified zinc-finger and BTB domain-containing protein 17 (ZBTB17) as a novel interacting partner. ZBTB17 is a transcription factor that contains the peak association signal (rs10927875) at the replicated 1p36 cardiomyopathy locus. ZBTB17 expression protected cardiac myocytes from apoptosis in vitro and in a mouse model with cardiac myocyte-specific deletion of Zbtb17, which develops cardiomyopathy and fibrosis after biomechanical stress. ZBTB17 also regulated cardiac myocyte hypertrophy in vitro and in vivo in a calcineurin-dependent manner.

Conclusions: We revealed new functions for ZBTB17 in the heart, a transcription factor that may play a role as a novel cardiomyopathy gene.
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http://dx.doi.org/10.1161/CIRCGENETICS.113.000690DOI Listing
October 2015

Mechano-signaling in heart failure.

Pflugers Arch 2014 Jun 16;466(6):1093-9. Epub 2014 Feb 16.

Imperial College, British Heart Foundation-Centre for Research Excellence, National Heart and Lung Institute, Imperial Centre for Translational and Experimental Medicine, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK.

Mechanosensation and mechanotransduction are fundamental aspects of biology, but the link between physical stimuli and biological responses remains not well understood. The perception of mechanical stimuli, their conversion into biochemical signals, and the transmission of these signals are particularly important for dynamic organs such as the heart. Various concepts have been introduced to explain mechanosensation at the molecular level, including effects on signalosomes, tensegrity, or direct activation (or inactivation) of enzymes. Striated muscles, including cardiac myocytes, differ from other cells in that they contain sarcomeres which are essential for the generation of forces and which play additional roles in mechanosensation. The majority of cardiomyopathy causing candidate genes encode structural proteins among which titin probably is the most important one. Due to its elastic elements, titin is a length sensor and also plays a role as a tension sensor (i.e., stress sensation). The recent discovery of titin mutations being a major cause of dilated cardiomyopathy (DCM) also underpins the importance of mechanosensation and mechanotransduction in the pathogenesis of heart failure. Here, we focus on sarcomere-related mechanisms, discuss recent findings, and provide a link to cardiomyopathy and associated heart failure.
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http://dx.doi.org/10.1007/s00424-014-1468-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4033803PMC
June 2014

A critical role for Telethonin in regulating t-tubule structure and function in the mammalian heart.

Hum Mol Genet 2013 Jan 25;22(2):372-83. Epub 2012 Oct 25.

Laboratory of Cell Electrophysiology, Heart Science Centre, Harefield Hospital, London UB9 6JH, UK.

The transverse (t)-tubule system plays an essential role in healthy and diseased heart muscle, particularly in Ca(2+)-induced Ca(2+) release (CICR), and its structural disruption is an early event in heart failure. Both mechanical overload and unloading alter t-tubule structure, but the mechanisms mediating the normally tight regulation of the t-tubules in response to load variation are poorly understood. Telethonin (Tcap) is a stretch-sensitive Z-disc protein that binds to proteins in the t-tubule membrane. To assess its role in regulating t-tubule structure and function, we used Tcap knockout (KO) mice and investigated cardiomyocyte t-tubule and cell structure and CICR over time and following mechanical overload. In cardiomyocytes from 3-month-old KO (3mKO), there were isolated t-tubule defects and Ca(2+) transient dysynchrony without whole heart and cellular dysfunction. Ca(2+) spark frequency more than doubled in 3mKO. At 8 months of age (8mKO), cardiomyocytes showed progressive loss of t-tubules and remodelling of the cell surface, with prolonged and dysynchronous Ca(2+) transients. Ca(2+) spark frequency was elevated and the L-type Ca(2+) channel was depressed at 8 months only. After mechanical overload obtained by aortic banding constriction, the Ca(2+) transient was prolonged in both wild type and KO. Mechanical overload increased the Ca(2+) spark frequency in KO alone, where there was also significantly more t-tubule loss, with a greater deterioration in t-tubule regularity. In conjunction, Tcap KO showed severe loss of cell surface ultrastructure. These data suggest that Tcap is a critical, load-sensitive regulator of t-tubule structure and function.
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http://dx.doi.org/10.1093/hmg/dds434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526164PMC
January 2013

Z-disc transcriptional coupling, sarcomeroptosis and mechanoptosis [corrected].

Cell Biochem Biophys 2013 May;66(1):65-71

Myocardial Genetics, British Heart Foundation-Centre of Research Excellence, National Heart & Lung Institute, Imperial College, Hammersmith Campus, London, UK.

Cardiovascular diseases are the leading cause of morbidity and mortality worldwide. Heart failure, which contributes significantly to the incidence and prevalence of cardiovascular-related diseases, can be the result of a myriad of diverse aetiologies including viral infections, coronary heart disease and genetic abnormalities--just to name a few. Interestingly, almost every type of heart failure is characterized by the loss of cardiac myocytes, either via necrosis, apoptosis or autophagy. While the former for a long time mainly has been characterized by passive loss of cells and only the latter two have been regarded as active processes, a new view is now emerging, whereby all three forms of cell death are regarded as different types of programmed cell death which can be induced via different stimuli and pathways, most of which are probably not well understood (Kung et al., Circulation Research 108(8):1017-1036, 2011). Here, we focus on the sarcomeric Z-disc, Z-disc transcriptional coupling and its role in pro-survival pathways as well as in striated muscle specific forms of cell death (sarcomeroptosis) and mechanically induced apoptosis or mechanoptosis.
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http://dx.doi.org/10.1007/s12013-012-9430-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3627051PMC
May 2013

The sarcomeric Z-disc and Z-discopathies.

J Biomed Biotechnol 2011 18;2011:569628. Epub 2011 Oct 18.

Centre for Research Excellence, British Heart Foundation, National Heart & Lung Institute, Imperial College, South Kensington Campus, Flowers Building, 4th Floor, London SW72AZ, UK.

The sarcomeric Z-disc defines the lateral borders of the sarcomere and has primarily been seen as a structure important for mechanical stability. This view has changed dramatically within the last one or two decades. A multitude of novel Z-disc proteins and their interacting partners have been identified, which has led to the identification of additional functions and which have now been assigned to this structure. This includes its importance for intracellular signalling, for mechanosensation and mechanotransduction in particular, an emerging importance for protein turnover and autophagy, as well as its molecular links to the t-tubular system and the sarcoplasmic reticulum. Moreover, the discovery of mutations in a wide variety of Z-disc proteins, which lead to perturbations of several of the above-mentioned systems, gives rise to a diverse group of diseases which can be termed Z-discopathies. This paper provides a brief overview of these novel aspects as well as points to future research directions.
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http://dx.doi.org/10.1155/2011/569628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3199094PMC
February 2012

Telethonin deficiency is associated with maladaptation to biomechanical stress in the mammalian heart.

Circ Res 2011 Sep 28;109(7):758-69. Epub 2011 Jul 28.

Imperial College, National Heart & Lung Institute, British Heart Foundation, Centre for Research Excellence, Myocardial Genetics, London, UK.

Rationale: Telethonin (also known as titin-cap or t-cap) is a 19-kDa Z-disk protein with a unique β-sheet structure, hypothesized to assemble in a palindromic way with the N-terminal portion of titin and to constitute a signalosome participating in the process of cardiomechanosensing. In addition, a variety of telethonin mutations are associated with the development of several different diseases; however, little is known about the underlying molecular mechanisms and telethonin's in vivo function.

Objective: Here we aim to investigate the role of telethonin in vivo and to identify molecular mechanisms underlying disease as a result of its mutation.

Methods And Results: By using a variety of different genetically altered animal models and biophysical experiments we show that contrary to previous views, telethonin is not an indispensable component of the titin-anchoring system, nor is deletion of the gene or cardiac specific overexpression associated with a spontaneous cardiac phenotype. Rather, additional titin-anchorage sites, such as actin-titin cross-links via α-actinin, are sufficient to maintain Z-disk stability despite the loss of telethonin. We demonstrate that a main novel function of telethonin is to modulate the turnover of the proapoptotic tumor suppressor p53 after biomechanical stress in the nuclear compartment, thus linking telethonin, a protein well known to be present at the Z-disk, directly to apoptosis ("mechanoptosis"). In addition, loss of telethonin mRNA and nuclear accumulation of this protein is associated with human heart failure, an effect that may contribute to enhanced rates of apoptosis found in these hearts.

Conclusions: Telethonin knockout mice do not reveal defective heart development or heart function under basal conditions, but develop heart failure following biomechanical stress, owing at least in part to apoptosis of cardiomyocytes, an effect that may also play a role in human heart failure.
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http://dx.doi.org/10.1161/CIRCRESAHA.111.245787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3664427PMC
September 2011

MLP (muscle LIM protein) as a stress sensor in the heart.

Pflugers Arch 2011 Jul 13;462(1):135-42. Epub 2011 Apr 13.

Myocardial Genetics, British Heart Foundation-Centre for Research Excellence, National Heart & Lung Institute, Imperial College, South Kensington Campus, Flowers Building, 4th floor, London, SW7 2AZ, UK.

Muscle LIM protein (MLP, also known as cysteine rich protein 3 (CSRP3, CRP3)) is a muscle-specific-expressed LIM-only protein. It consists of 194 amino-acids and has been described initially as a factor involved in myogenesis (Arber et al. Cell 79:221-231, 1994). MLP soon became an important model for experimental cardiology when it was first demonstrated that MLP deficiency leads to myocardial hypertrophy followed by a dilated cardiomyopathy and heart failure phenotype (Arber et al. Cell 88:393-403, 1997). At this time, this was the first genetically altered animal model to develop this devastating disease. Interestingly, MLP was also found to be down-regulated in humans with heart failure (Zolk et al. Circulation 101:2674-2677, 2000) and MLP mutations are able to cause hypertrophic and dilated forms of cardiomyopathy in humans (Bos et al. Mol Genet Metab 88:78-85, 2006; Geier et al. Circulation 107:1390-1395, 2003; Hershberger et al. Clin Transl Sci 1:21-26, 2008; Knöll et al. Cell 111:943-955, 2002; Knöll et al. Circ Res 106:695-704, 2010; Mohapatra et al. Mol Genet Metab 80:207-215, 2003). Although considerable efforts have been undertaken to unravel the underlying molecular mechanisms-how MLP mutations, either in model organisms or in the human setting cause these diseases are still unclear. In contrast, only precise knowledge of the underlying molecular mechanisms will allow the development of novel and innovative therapeutic strategies to combat this otherwise lethal condition. The focus of this review will be on the function of MLP in cardiac mechanosensation and we shall point to possible future directions in MLP research.
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http://dx.doi.org/10.1007/s00424-011-0961-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3114083PMC
July 2011

Genetics of mechanosensation in the heart.

J Cardiovasc Transl Res 2011 Jun 1;4(3):238-44. Epub 2011 Mar 1.

Myocardial Genetics, British Heart Foundation-Centre for Research Excellence, National Heart & Lung Institute, Imperial College, South Kensington Campus, London, UK.

Mechanosensation (the ultimate conversion of a mechanical stimulus into a biochemical signal) as well as mechanotransduction (transmission of mechanically induced signals) belong to the most fundamental processes in biology. These effects, because of their dynamic nature, are particularly important for the cardiovascular system. Therefore, it is not surprising that defects in cardiac mechanosensation, are associated with various types of cardiomyopathy and heart failure. However, our current knowledge regarding the genetic basis of impaired mechanosensation in the cardiovascular system is beginning to shed light on this subject and is at the centre of this brief review.
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http://dx.doi.org/10.1007/s12265-011-9262-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3098994PMC
June 2011

Pelota interacts with HAX1, EIF3G and SRPX and the resulting protein complexes are associated with the actin cytoskeleton.

BMC Cell Biol 2010 Apr 20;11:28. Epub 2010 Apr 20.

Institute of Human Genetics, Georg-August-University, Göttingen, Germany.

Background: Pelota (PELO) is an evolutionary conserved protein, which has been reported to be involved in the regulation of cell proliferation and stem cell self-renewal. Recent studies revealed the essential role of PELO in the No-Go mRNA decay, by which mRNA with translational stall are endonucleotically cleaved and degraded. Further, PELO-deficient mice die early during gastrulation due to defects in cell proliferation and/or differentiation.

Results: We show here that PELO is associated with actin microfilaments of mammalian cells. Overexpression of human PELO in Hep2G cells had prominent effect on cell growth, cytoskeleton organization and cell spreading. To find proteins interacting with PELO, full-length human PELO cDNA was used as a bait in a yeast two-hybrid screening assay. Partial sequences of HAX1, EIF3G and SRPX protein were identified as PELO-interacting partners from the screening. The interactions between PELO and HAX1, EIF3G and SRPX were confirmed in vitro by GST pull-down assays and in vivo by co-immunoprecipitation. Furthermore, the PELO interaction domain was mapped to residues 268-385 containing the c-terminal and acidic tail domain. By bimolecular fluorescence complementation assay (BiFC), we found that protein complexes resulting from the interactions between PELO and either HAX1, EIF3G or SRPX were mainly localized to cytoskeletal filaments.

Conclusion: We could show that PELO is subcellularly localized at the actin cytoskeleton, interacts with HAX1, EIF3G and SRPX proteins and that this interaction occurs at the cytoskeleton. Binding of PELO to cytoskeleton-associated proteins may facilitate PELO to detect and degrade aberrant mRNAs, at which the ribosome is stalled during translation.
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http://dx.doi.org/10.1186/1471-2121-11-28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2867792PMC
April 2010

Prm3, the fourth gene in the mouse protamine gene cluster, encodes a conserved acidic protein that affects sperm motility.

Biol Reprod 2008 Jun 6;78(6):958-67. Epub 2008 Feb 6.

Institute of Human Genetics, University of Göttingen, Göttingen D-37073, Germany.

The protamine gene cluster containing the Prm1, Prm2, Prm3, and Tnp2 genes is present in humans, mice, and rats. The Prm1, Prm2, and Tnp2 genes have been extensively studied, but almost nothing is known about the function and regulation of the Prm3 gene. Here we demonstrate that an intronless Prm3 gene encoding a distinctive small acidic protein is present in 13 species from seven orders of mammals. We also demonstrate that the Prm3 gene has not generated retroposons, which supports the contention that genes that are expressed in meiotic and haploid spermatogenic cells do not generate retroposons. The Prm3 mRNA is first detected in early round spermatids, while the PRM3 protein is first detected in late spermatids. Thus, translation of the Prm3 mRNA is developmentally delayed similar to the Prm1, Prm2, and Tnp2 mRNAs. In contrast to PRM1, PRM2, and TNP2, PRM3 is an acidic protein that is localized in the cytoplasm of elongated spermatids and transfected NIH-3T3 cells. To elucidate the function of PRM3, the Prm3 gene was disrupted by homologous recombination. Sperm from Prm3(-/-) males exhibited reductions in motility, but the fertility of Prm3(-/-) and Prm3(+/+) males was similar in matings of one male and one female. We have developed a competition test in which a mutant male has to compete with a rival wild-type male to fertilize a female; the implications of these results are also discussed.
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http://dx.doi.org/10.1095/biolreprod.107.065706DOI Listing
June 2008