Molecular architecture of meiotic chromosomes

Faithful chromosome segregation at each cell division is essential as the formation of cells with an abnormal number of chromosomes (aneuploid cells) can result in infertility, developmental defects or cancer. Aneuploidy occurs in approximately 20% of all conceptions, causing infertility and embryo death. Chromosomal disorders are the most common known cause of mental retardation, e.g. Downs syndrome, affecting 0,3% of all newborns.

Meiosis is a highly specialized germ cell specific cell division that generates genetically diverse haploid gametes. The aim of this thesis was to study the functions of a set of structural and regulatory proteins that are associated with the meiotic chromosomes. Mammalian meiotic chromosomes at meiosis I are organised and supported by several protein structures including synaptonemal and cohesin complexes. The synaptonernal complex (SC), formed only in meiosis, promotes synapsis and recombination between the homologues. The SC is composed of two axial elements (AEs) and the central element (CE) connected by transverse filaments (TFs). The AEs are composed of Sycp2 and Sycp3 whereas the TFs are formed by Sycp1. The cohesin complexes are formed by Smc1α, Smc3, Scc1/Rad21 and Scc3/SA1 or SA2 and three meiosis-specific subunits Smc1β, Rec8 and Stag3 The cohesin complexes are important for sister chromatid pairing and separation during mitosis and meiosis and are likely to be the key organisers of the chromatin loop arrays along the meiotic chromosome axis.

So far, it has been difficult to reproduce the germ cell differentiation process in vitro using cell culture models. Our attempt to differentiate embryonic stem cells (ESCs) to germ cells, in order to analyze meiotic chromosome architecture in vitro, revealed the inaccurate meiotic development of germ celllike cells derived from ESCs in culture. This suggests that, while several aspects of the germ cell differentiation process can be reproduced in vitro, more work is required to validate the meiotic cell division process in the identified germ cell-like cells.

The Sycp3-deficient mouse strain was used as a model to monitor the integrity of the meiotic chromosome axis. We found that the cohesins disassembled prematurely in the absence of Sycp3. This supports a model where Sycp3 has a structural role in maintaining, but not establishing the cohesin core. Mutant mice lacking both Sycp3 and Smc1β p proteins have provided novel insights into the organization of the meiotic chromosomes. It was shown that loss of Sycp3 or Smc1β impairs the structural integrity of the meiotic chromosomes by affecting the length of the chromosome axes. We showed that different cohesin complexes coexist along the meiotic chromosome axis and generate an axial core that physically anchors the chromatin loops to the axes. Analysis of chromosome asynapsis and crossover patterns in Sycp3-/-Smc1β-/- revealed that this loss affects the accuracy of chromosome segregation and activates two independent checkpoints that eliminate damaged oocytes.

Meiotic checkpoints and DNA damage repair are often hypothesized to be regulated from the central region of the SC. Previously, no proteins have been assigned to central region of the SC. We identified three novel central element (CE) proteins, Syce1, Sycp2 and Tex12. We found that Sycp1 is essential for their integration into the SC. Results revealed a novel molecular network within the CE.

List of scientific papers

I. Novak I, Lightfoot DA, Wang H, Eriksson A, Mahdy E, Hoog C (2006). Mouse embryonic stem cells form follicle-like ovarian structures but do not progress through meiosis. Stem Cells. 24(8): 1931-6.
https://pubmed.ncbi.nlm.nih.gov/16644921

II. Kouznetsova A, Novak I, Jessberger R, Hoog C. (2005). SYCP2 and SYCP3 are required for cohesin core integrity at diplotene but not for centromere cohesion at the first meiotic division. J Cell Sci. 118(pt 10): 2271-8.
https://pubmed.ncbi.nlm.nih.gov/15870106

III. Novak I, Wang H, Revekova E, Jessberger R, Liebe B, Scherthan H, Hoog C (2006). Synaptonemal complex proteins and cohesin SMC1BETA shape meiotic chromosome architecture. [Submitted]

IV. Costa Y, Speed R, Ollinger R, Alsheimer M, Semple CA, Gautier P, Maratou K, Novak I, Hoog C, Benavente R, Cooke HJ (2005). Two novel proteins recruited by synaptonemal complex protein 1 (SYCP1) are at the centre of meiosis. J Cell Sci. 118(pt 12): 2755-62.
https://pubmed.ncbi.nlm.nih.gov/15944401

V. Hamer G, Gell K, Kouznetsova A, Novak I, Benavente R, Hoog C (2006). Characterization of a novel meiosis-specific protein within the central element of the synaptonemal complex. J Cell Sci. 119(Pt 19): 4025-32.
https://pubmed.ncbi.nlm.nih.gov/16968740