Los fundamentos racionales y sociológicos de la música
In: Clásicos del pensamiento 132
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In: Clásicos del pensamiento 132
Copyright © 2020 The Authors. ; Meiotic reductional division depends on the synaptonemal complex (SC), a supramolecular protein assembly that mediates homologous chromosomes synapsis and promotes crossover formation. The mammalian SC has eight structural components, including SYCE1, the only central element protein with known causative mutations in human infertility. We combine mouse genetics, cellular, and biochemical studies to reveal that SYCE1 undergoes multivalent interactions with SC component SIX6OS1. The N terminus of SIX6OS1 binds and disrupts SYCE1's core dimeric structure to form a 1:1 complex, while their downstream sequences provide a distinct second interface. These interfaces are separately disrupted by SYCE1 mutations associated with nonobstructive azoospermia and premature ovarian failure (POF), respectively. Mice harboring SYCE1's POF mutation and a targeted deletion within SIX6OS1's N terminus are infertile with failure of chromosome synapsis. We conclude that both SYCE1-SIX6OS1 binding interfaces are essential for SC assembly, thus explaining how SYCE1's reported clinical mutations give rise to human infertility. ; O.R.D. is a Sir Henry Dale Fellow jointly funded by the Wellcome Trust and Royal Society (grant number 104158/Z/14/Z). This work was supported by MINECO (BFU2017-89408-R) and by Junta de Castilla y Leon (CSI239P18). F.S.-S., L.G.-H., and N.F.-M. are supported by European Social Fund/JCyLe grants (EDU/556/2019, EDU/1083/2013, and EDU/310/2015). CIC-IBMCC is supported by the Programa de Apoyo a Planes Estratégicos de Investigación de Estructuras de Investigación de Excelencia cofunded by the Castilla–León autonomous government and the European Regional Development Fund (CLC–2017–01).
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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. The ubiquitin proteasome system regulates meiotic recombination in yeast through its association with the synaptonemal complex, a 'zipper'-like structure that holds homologous chromosome pairs in synapsis during meiotic prophase I. In mammals, the proteasome activator subunit PA200 targets acetylated histones for degradation during somatic DNA double strand break repair and during histone replacement during spermiogenesis. We investigated the role of the testis-specific proteasomal subunit a4s (PSMA8) during spermatogenesis, and found that PSMA8 was localized to and dependent on the central region of the synaptonemal complex. Accordingly, synapsis-deficient mice show delocalization of PSMA8. Moreover, though Psma8-deficient mice are proficient in meiotic homologous recombination, there are alterations in the proteostasis of several key meiotic players that, in addition to the known substrate acetylated histones, have been shown by a proteomic approach to interact with PSMA8, such as SYCP3, SYCP1, CDK1 and TRIP13. These alterations lead to an accumulation of spermatocytes in metaphase I and II which either enter massively into apoptosis or give rise to a low number of aberrant round spermatids that apoptose before histone replacement takes place ; This work was supported by MINECO (BFU2017-89408-R) and by Junta de Castilla y Leon (CSI239P18). LGH and NFM are supported by European Social Fund/JCyLe grants (EDU/1083/ 2013 and EDU/310/2015) and YBC by a FPI grant from the MINECO (BS-2015-073993). IR was supported by MINECO (BFU2016-80370-P). JAS was supported by MINECO (BFU2014-53681-P). We appreciate the help of Mª Luz Sánchez García for the FACs analysis. The proteomic analysis was performed in the Proteomics Facility of Centro de Investigación del Cáncer, Salamanca, Grant PRB3 (IPT17/0019 - ISCIII-SGEFI / ERDF). CIC-IBMCC is supported by the Programa de Apoyo a Planes Estratégicos de Investigación de Estructuras de Investigación de Excelencia cofunded by the Castilla–León autonomous government and the European Regional Development Fund (CLC– 2017–01). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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© 2019 the Author(s). ; Faithful chromosome segregation during meiosis I depends upon the formation of connections between homologous chromosomes. Crossovers between homologs connect the partners, allowing them to attach to the meiotic spindle as a unit, such that they migrate away from one another at anaphase I. Homologous partners also become connected by pairing of their centromeres in meiotic prophase. This centromere pairing can promote proper segregation at anaphase I of partners that have failed to become joined by a crossover. Centromere pairing is mediated by synaptonemal complex (SC) proteins that persist at the centromere when the SC disassembles. Here, using mouse spermatocyte and yeast model systems, we tested the role of shugoshin in promoting meiotic centromere pairing by protecting centromeric synaptonemal components from disassembly. The results show that shugoshin protects the centromeric SC in meiotic prophase and, in anaphase, promotes the proper segregation of partner chromosomes that are not linked by a crossover. ; The authors thank the members of the Program in Cell Cycle and Cancer Biology for their constructive comments during this project. A.M.P. is funded by Award BFU2017-89408-R from the Spanish Ministry of Economy and Competitiveness and his program is supported by the Programa de Apoyo a Planes Estratégicos de Investigación de Estructuras de Investigación de Excelencia, which is cofunded by the Castilla–León autonomous government and the European Regional Development Fund (Award CLC–2017–01). R.J.P. was supported by Centers of Biomedical Research Excellence Grant GM103636 and March of Dimes Grant FY14-256. D.S.D. was supported by NIH Grant R01 GM087377.
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© Felipe-Medina et al. ; Primary Ovarian Insufficiency (POI) is a major cause of infertility, but its etiology remains poorly understood. Using whole-exome sequencing in a family with three cases of POI, we identified the candidate missense variant S167L in HSF2BP, an essential meiotic gene. Functional analysis of the HSF2BP-S167L variant in mouse showed that it behaves as a hypomorphic allele compared to a new loss-of-function (knock-out) mouse model. Hsf2bpS167L/S167L females show reduced fertility with smaller litter sizes. To obtain mechanistic insights, we identified C19ORF57/BRME1 as a strong interactor and stabilizer of HSF2BP and showed that the BRME1/HSF2BP protein complex co-immunoprecipitates with BRCA2, RAD51, RPA and PALB2. Meiocytes bearing the HSF2BP-S167L variant showed a strongly decreased staining of both HSF2BP and BRME1 at the recombination nodules and a reduced number of the foci formed by the recombinases RAD51/DMC1, thus leading to a lower frequency of crossovers. Our results provide insights into the molecular mechanism of HSF2BP-S167L in human ovarian insufficiency and sub(in)fertility. ; This study was supported by Université Paris Diderot and the Fondation pour la Recherche Médicale (Labelisation Equipes DEQ20150331757, SC, A-LT and RAV). This work was supported by MINECO (BFU2017-89408-R) and by Junta de Castilla y León (CSI239P18). NFM, FSS and LGH are supported by European Social Fund/JCyLe grants (EDU/310/2015, EDU/556/2019 and EDU/1083/2013). YBC is funded by a grant from MINECO (BS-2015–073993). The proteomic analysis was performed in the Proteomics Facility of Centro de Investigación del Cáncer, Salamanca, Grant PRB3(IPT17/0019 - ISCIII-SGEFI/ERDF). CIC-IBMCC is supported by the Programa de Apoyo a Planes Estratégicos de Investigación de Estructuras de Investigación de Excelencia cofunded by the Castilla–León autonomous government and the European Regional Development Fund (CLC–2017–01).
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Previous studies suggested that the aryl hydrocarbon receptor (AhR) contributes to mice reproduction and fertility. However, the mechanisms involved remain mostly unknown. Retrotransposon silencing by Piwi-interacting RNAs (piRNAs) is essential for germ cell maturation and, remarkably, AhR has been identified as a regulator of murine B1-SINE retrotransposons. Here, using littermate AhR and AhR mice, we report that AhR regulates the general course of spermatogenesis and oogenesis by a mechanism likely to be associated with piRNA-associated proteins, piRNAs and retrotransposons. piRNA-associated proteins MVH and Miwi are upregulated in leptotene to pachytene spermatocytes with a more precocious timing in AhR than in AhR testes. piRNAs and transcripts from B1-SINE, LINE-1 and IAP retrotransposons increased at these meiotic stages in AhR-null testes. Moreover, B1-SINE transcripts colocalize with MVH and Miwi in leptonema and pachynema spermatocytes. Une pectedly, AhR males have increased sperm counts, higher sperm functionality and enhanced fertility than AhR mice. In contrast, piRNA-associated proteins and B1-SINE and IAP-derived transcripts are reduced in adult AhR2/2 ovaries. Accordingly, AhR-null female mice have lower numbers of follicles when compared with AhR\+/\+ mice. Thus, AhR deficiency differentially affects testis and ovary development possibly by a process involving piRNA-associated proteins, piRNAs and transposable elements. ; This work was supported by grants to P.M.F-S. from the Spanish Ministry of Science and Innovation (BFU2011-22678) and Economy and Competitiveness (SAF2014-51813-R) and from the Junta de Extremadura (GR15008). Research at the F.J.P. laboratory was supported by grant no. AGL2013-43211-R from the Spanish Ministry of Economy and Competitiveness. Research at the P.M.F-S laboratory was also supported by the Red Tematica de Investigacion Cooperativa en Cancer (RTICC), Carlos III Institute, Spanish Ministry of Economy and Competitiveness (RD12/0036/0032). E.R.L., F.J.G-R and E.B. were supported by the RTICC, MICINN and Junta de Extremadura, respectively. N.M.M. was an FPI fellow of the Spanish Ministry of Education. P.M.M. was supported by a pre-doctoral grant from the Spanish Ministry of Education, Culture and Sport (FPU13/03991) C.O.F. was supported by a postdoctoral Juan de la Cierva (IJCI-2014-21671) grant from the Spanish Ministry of Economy and Competitiveness. A.M.P. and E.L. were supported by grants from the Spanish Ministry of Economy and Competitiveness (BFU2014-59307-R), MEIONet and the Junta de Castilla y Leon. All Spanish funding is co-sponsored by the European Union FEDER programme. ; Peer Reviewed
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