A Novel Mouse Synaptonemal Complex Protein Is Essential for Loading of Central Element Proteins, Recombination, and Fertility Sabine Schramm1, Johanna Fraune1, Ronald Naumann 2 , Abrahan Hernandez-Hernandez3, Christer Ho¨ o¨ g3, Howard J. Cooke4,5, Manfred Alsheimer1*, Ricardo Benavente1* 1 Department of Cell and Developmental Biology, Biocenter, University of Wu¨ rzburg, Wu¨ rzburg, Germany, 2 Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany, 3 Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden, 4 Medical Research Council Human Genetics Unit and Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, United Kingdom, 5 Hefei National Laboratory for Physical Sciences at Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China Abstract The synaptonemal complex (SC) is a proteinaceous, meiosis-specific structure that is highly conserved in evolution. During meiosis, the SC mediates synapsis of homologous chromosomes. It is essential for proper recombination and segregation of homologous chromosomes, and therefore for genome haploidization. Mutations in human SC genes can cause infertility. In order to gain a better understanding of the process of SC assembly in a model system that would be relevant for humans, we are investigating meiosis in mice. Here, we report on a newly identified component of the murine SC, which we named SYCE3. SYCE3 is strongly conserved among mammals and localizes to the central element (CE) of the SC. By generating a Syce3 knockout mouse, we found that SYCE3 is required for fertility in both sexes. Loss of SYCE3 blocks synapsis initiation and results in meiotic arrest. In the absence of SYCE3, initiation of meiotic recombination appears to be normal, but its progression is severely impaired resulting in complete absence of MLH1 foci, which are presumed markers of crossovers in wild-type meiocytes. In the process of SC assembly, SYCE3 is required downstream of transverse filament protein SYCP1, but upstream of the other previously described CE–specific proteins. We conclude that SYCE3 enables chromosome loading of the other CE–specific proteins, which in turn would promote synapsis between homologous chromosomes. Citation: Schramm S, Fraune J, Naumann R, Hernandez-Hernandez A, Ho¨ o¨ g C, et al. (2011) A Novel Mouse Synaptonemal Complex Protein Is Essential for Loading of Central Element Proteins, Recombination, and Fertility. PLoS Genet 7(5): e1002088. doi:10.1371/journal.pgen.1002088 Editor: Anne M. Villeneuve, Stanford University, United States of America Received August 20, 2010; Accepted March 31, 2011; Published May 26, 2011 Copyright: 2011 Schramm et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was funded by the German Research Foundation (DFG) and the University of Wu¨ rzburg in the funding programme Open Access Publishing. It was supported by grants Be1168/6-3 (DFG), Be1168/7-1 (Priority Program 1384 - Mechanisms of genome haploidization - , DFG (http://www.dfg.de)), and the Graduate School GK 1048 of the University of Wuerzburg (http://www.gk-1048.uni-wuerzburg.de). CH and AH-H were funded by grants from the Swedish Cancer Society (http://www.cancerfonden.se/sv/), The Swedish Research Council (http://www.formas.se/), Torsten och Ragnar Soederbergs Stiftelser (http://www. soderbergsstiftelser.se/), and Karolinska Institutet (http://ki.se/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: benavente@biozentrum.uni-wuerzburg.de (RB); alsheimer@biozentrum.uni-wuerzburg.de (MA) Introduction Meiosis is a special type of cell division which gives rise to haploid, genetically diverse gametes. For organisms that reproduce sexually the correct haploidization of paternal and maternal genomes is of utmost importance. To ensure the correct separation of homologous chromosomes during anaphase I, homologs first have to find each other before coming into close physical proximity. This process takes place during prophase I of meiosis, which is highly regulated and can be subdivided into five stages: leptotene (chromosome condensation), zygotene (initiation of synapsis), pachytene (full synapsis), diplotene (desynapsis), and diakinesis (visible chiasmata) [1]. One key component that enables synapsis and crossover formation is the synaptonemal complex (SC), a largely proteinaceous, meiosis-specific nuclear structure. The SC consists of three components: two lateral elements (LEs), each of which are associated with a pair of sister chromatids, and a central region between the two LEs, that is composed of numerous transverse filaments and the central element (CE). The central region physically links homologous chromosomes in a zipper-like manner and thus mediates synapsis (reviewed in [2,3]). The tripartite structure of the SC is strikingly conserved from budding yeast to humans emphasizing its prominent function during meiosis. Much of our current understanding in the field was obtained from organisms such as Saccharomyces cerevisiae, Caenorhab- ditis elegans, and Drosophila melanogaster [4–10]. However, the mouse also has advanced to a widespread model system for the analysis of SC composition and regulation [11,12]. Investigations in the mouse are expected to provide a better insight into causes of infertility in humans [13–15]. Several mouse models have been generated over recent years in order to illuminate the process of mammalian SC assembly. With the aid of these a first molecular model of SC assembly, synapsis initiation and propagation was proposed [11]. SC assembly in mice is initiated during leptotene with the formation of the axial elements (AEs; i.e. the precursor structures of LEs) by the AE proteins SYCP2 and SYCP3 [2,16]. The AEs colocalize with cohesin cores consisting of cohesin complex PLoS Genetics | www.plosgenetics.org 1 May 2011 | Volume 7 | Issue 5 | e1002088