Alberto M. Pendás, PI and coordinator of the MeioNet
Jose Luis Barbero
Track record of the group
The Pendas’ lab (own group started in 2006) has dissected the Shugoshin-like-2 (Sgol2) function, demonstrating that it is essential to protect the centromere cohesins in mammalian meiosis at anaphase I. Mechanically, SGOL2 deficiency causes a premature release of meiotic cohesin REC8 from the metaphase I centromere that leads to aneuploid gametes and infertility (10). Additionally, SGOL2 makes a platform that coordinates other essential functions in chromosomal dynamics (1) without affecting chromosome mono-orientation. This striking observation led as to the search and identification of the MEIKIN complex responsible for this mono-Orientation (Watanabe´s lab collaboration) of the sister kinetochores in the meiosis of mammals (6). Likewise, we have characterized a new subunit of the mammalian cohesin complex (9). The new RAD21L protein presents homology with the α-kleisin subfamily RAD21/REC8 and interacts with other subunits of the complex (SMC3, SMC1A) and, specifically with the STAG3 subunit (9). As a consequence, RAD21L is located in the axial elements (AE) of the synaptonemal complex (SC) during the prophase I. In vivo, RAD21L is essential to carry out meiotic synapsis and DNA repair in spermatocytes but not in mouse oocytes (8). Consequently, RAD21L deficiency causes male infertility with non-obstructive azoospermia (NOA) and female subfertility due to premature ovarian failure (POF) (8). This study challenges REC8 being the only meiotic α-kleisin in mammals, and suggests that the existence of two meiotic α-kleisins explains why yeast, but not the mutant mice of Rec8, do not assemble their SC’s AEs. We have validated this hypothesis by showing that the double KOs for both Rec8 and Rad21L cohesins do not assemble their AEs (7). This contribution shows the essential role that cohesins play in AE assembly and its conservation from yeast to mammals (7). Given the relevance of cohesins in mouse meiosis (3, 7, 10), we addresses their role in human fertility. By exome sequencing analysis of an inbred family with POF, we identified a 1-bp homozygous deletion in the human STAG3 gene that generates a premature stop codon. By modeling the disease in the mouse we stablished for the first time a causal relationship between cohesins and human infertility . Although, males in the family with mutations in STAG3 were heterozygous (fertile), we used the developed loss of function mouse model to predict that human males with STAG3-deficiency (as occurred to the males mice) would show early meiotic arrest in prophase I with NOA and thus infertility . Thus, we have proposed that NOA and POF can be genetically the same disease. More recently, we have initiated the characterization of anonymous loci from GWAS studies of human fertility such as the non-synonimous SNP rs1254319. We showed that this anonymous cSNP within the ORF named SIX6OS1, encodes a novel central element protein of the SC that specifically interacts with the central element protein 1 (SYCE1) (2). By using genomic editing techniques, we showed that mice lacking SIX6OS1 are defective in chromosome synapsis at meiotic prophase I, which provokes an arrest at the pachytene-like stage and results in infertility. In accordance with its role as a modifier of the human recombination rate, SIX6OS1 is essential for the appropriate processing of intermediate recombination nodules before crossover formation (2)
Most relevant publications
1) APC/CCdh1 Enables Removal of Shugoshin-2 from the Arms of Bivalent Chromosomes by Moderating Cyclin-Dependent Kinase Activity. Rattani A, Ballesteros Mejia R, Roberts K, Roig MB, Godwin J, Hopkins M, Eguren M, Sanchez-Pulido L, Okaz E, Ogushi S, Wolna M, Metson J, Pendás AM, Malumbres M, Novák B, Herbert M, Nasmyth K. Curr Biol. 2017 May 22;27(10):1462-1476.e5. doi:10.1016/j.cub.2017.04.023
2) C14ORF39/SIX6OS1 is a constituent of the synaptonemal complex and is essential for mouse fertility. Gómez-H L*, Felipe-Medina N*, Sánchez-Martín M, Davies OR, Ramos I, García-Tuñón I, de Rooij DG, Dereli I, Tóth A, Barbero JL, Benavente R, Llano E$, Pendas AM$. Nat Commun. 2016 Oct 31;7:13298. doi: 10.1038/ncomms13298.*these authors contribute equally. ($ corresponding author)
3) Distinct Roles of Meiosis-Specific Cohesin Complexes in Mammalian Spermatogenesis. Biswas U, Hempel K, Llano E, Pendas AM, Jessberger R. PLoS Genet. 2016 Oct 28;12(10):e1006389. doi: 10.1371/journal.pgen.1006389
4) STAG3 is a strong candidate gene for male infertility. Llano E, Gomez-H L, García-Tuñón I, Sánchez-Martín M, Caburet S, Barbero JL, Schimenti JC, Veitia RA, Pendas AM. Hum Mol Genet. 2014 Jul 1;23(13):3421-31. doi: 10.1093/hmg/ddu051
5) Mutant cohesin in premature ovarian failure. Caburet S*, Arboleda VA*, Llano E*, Overbeek PA, Barbero JL, Oka K, Harrison W, Vaiman D, Ben-Neriah Z, García-Tuñón I, Fellous M, Pendás AM$, Veitia RA, Vilain E$. N Engl J Med. 2014 Mar 6;370(10):943-949. doi: 10.1056/NEJMoa1309635. (*these authors contribute equally. $ corresponding author)
6) Meikin is a conserved regulator of meiosis-I-specific kinetochore function. Kim J, Ishiguro K, Nambu A, Akiyoshi B, Yokobayashi S, Kagami A, Ishiguro T, Pendas AM, Takeda N, Sakakibara Y, Kitajima TS, Tanno Y, Sakuno T, Watanabe Y. Nature. 2015 Jan 22;517(7535):466-71. doi: 10.1038/nature14097
7) Meiotic cohesin complexes are essential for the formation of the axial element in mice. Llano E, Herrán Y, García-Tuñón I, Gutiérrez-Caballero C, de Álava E, Barbero JL, Schimenti J, de Rooij DG, Sánchez-Martín M, Pendás AM. J Cell Biol. 2012 Jun 25;197(7):877-85. doi: 10.1083/jcb.201201100
8) The cohesion subunit RAD21L functions in meiotic synapsis and exhibits sexual dimorphism in fertility. Herrán Y, Gutiérrez-Caballero C, Sánchez-Martín M, Hernández T, Viera A, Barbero JL, de Álava E, de Rooij DG, Suja JÁ, Llano E$, Pendás AM$. EMBO J. 2011 Jul 8;30(15):3091-105. doi: 10.1038/emboj.2011.222. ($corresponding author)
9) Identification and molecular characterization of the mammalian α-kleisin RAD21L. Gutiérrez-Caballero C, Herrán Y, Sánchez-Martín M, Suja JA, Barbero JL, Llano E, Pendás AM. Cell Cycle. 2011 May 1;10(9):1477-87. ($ corresponding author)
10) Shugoshin-2 is essential for the completion of meiosis but not for mitotic cell division in mice. Llano E*, Gómez R*, Gutiérrez-Caballero C, Herrán Y, Sánchez-Martín M, Vázquez-Quiñones L, Hernández T, de Alava E, Cuadrado A, Barbero JL, Suja JA, Pendás AM. Genes Dev. 2008 Sep 1;22(17):2400-13. doi: 10.1101/gad.475308. (*these authors contribute equally)
Diagrammatic representation of the paper: C14ORF39/SIX6OS1 is a constituent of the synaptonemal complex and is essential for mouse fertility.
Aim of the research work
Fertility is a complex function depending on the coordinated and combined action of the male and female reproductive systems and its dysfunction is a major health issue affecting one in seven couples in the first world. In addition, these reproductive problems are being exacerbated by societal changes in modern countries because both women and men have been delaying having children. The gametogenesis is among the most complex and highly regulated differentiation programs that make use of a unique reductional division or meiosis to give rise to highly specialized cells: the gametes. At present, we are far from understanding the genetic basis of mammalian gametogenesis and the molecular mechanisms underlying its pathological condition, infertility.
The main goal of the group is to expand our current knowledge of the “fertility loci kit” (coding and non-coding) and the mechanism by which these molecules are essential to carry out meiosis and gametogenesis/reproduction in humans making use of the mouse as a model organism.
Research identification links
Full list of publications in medline format