engleski

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. 0, 3% of all newborns are affected by chromosomal disorders, e.g. Downs syndrome, thereby being the most common known cause of mental retardation. Meiosis is highly specialized germ cell specific cell division that generates genetically diverse haploid gametes. The aim 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 synaptonemal 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 with transverse filaments (TFs). The AEs are composed of Sycp2 and Sycp3, whereas the TFs are formed by Sycp1. The cohesin complex consists of Smc1α, Smc3, Scc1/Rad21 and Scc3/SA1 or SA2 and three meiosis-specific cohesins 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. However, it was shown that both ovarian structures, containing oocyte-like cells could be generated from mouse embryonic stem cell (ESCs) lines in vitro. The initial goal of the Paper 1 was to employ this ESCs potential to study cells undergoing meiotic differentiation for detailed functional analysis of the meiotic chromosome organisation. However, when we studied the meiosis in the germ cell-like cells derived from ESCs in detail, we found that these cells do not represent functional germ cells. This suggests 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 system 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, cohesin core. Moreover, we showed no sexually dimorphic role for AEs at the MI stage of meiosis. Mutant mice lacking both Sycp3 and Smc1β proteins have provided novel insights into the organisation of the meiotic chromosomes. It was shown that loss of Sycp3 or Smc1β impair 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 the chromosome segregation and activates two independent checkpoints that eliminate the damaged oocytes. Previously, no proteins have been assigned to central region of the SC. We identified three novel central element (CE) proteins, Syce1, Sycp2 Tex12. We found that Sycp1 is essential for their integration into the SC. Results revealed a novel molecular network within the CE.

meiosis; cohesins; synaptonemal complex

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