Meiotic chromosome segregation : molecular analysis of the synaptonemal complex

Meiosis is a special type of cell division that produces haploid gametes from diploid parental cells. As such, meiosis stands at the gateway to sexual reproduction in most eukaryotic organisms. During meiosis, a complex, but tightly coordinated series of events occur. Homologous chromosomes come together and pair along their entire length. If all goes well, these same chromosomes exchange reciprocally and in doing so generate new gene combinations, as well as set the stage for the subsequent disjunction at meiosis I. The 'hows' and 'whens' of these remarkable events have been under investigation for over 100 years. One central character in these events is the synaptonemal complex (SC), which is a conspicuous player in the meiotic story.

The present study aims at understanding two major aspects of the SC: the constituents of the SC and the organisation and function of the individual components within the SC.

The SC consists of three parts: a central element (CE), two flanking lateral elements (LEs, which are called axial elements (AEs) prior to homologous chromosome pairing), and linking transverse filaments (TFs). Three protein components of the SC have been characterised, SCP1, 2 and 3. SCP1 has been shown to be a component of the TF, while both SCP2 and SCP3 are part of the LE.

We have used immunoelectron microscopy to study how the SCP1 protein molecules are organised within SC. We found that the N-terminal end of SCP1 was located within the CE of the SC, whereas the C-terminal end was close to the LEs. We also established in a yeast twohybrid assay that the N-terminal domain of SCP1 strongly interacted with itself. We have therefore proposed a model in which the TFs consist of one or more pairs of SCP1 dimers, each pair being organised in a head-to-head arrangement, with the C-termini anchored in the LEs and the two N-termini being joined in the CE.

We investigated the fiber-forming properties of SCP3 both in vitro and in vivo. We found that in cultured somatic cells SCP3 could self-assemble into multi-stranded and cross-striated fibers, which resemble the highly ordered LE in some organisms. An in vitro binding assay and an in vivo coexpression study also supported this self-polymerising feature of SCP3. The former showed that the C-terminal coiled-coil domain of SCP3 mediates homophilic protein-protein interactions, while the coexpression of SCP3 cDNAs encoding the coiled coil domain and the entire SCP3 could inhibit fiber formation in vivo. We therefore proposed that SCP3 fibers could constitute the core of the AE/LE and function as a molecular framework to which other proteins attach. To test this model, we successfully generated SCP3-deficient mice. The male mice were found to be sterile due to disruption of spermatogenesis at zygonema, which led to massive germ cell apoptosis. This suggests that lack of SCP3 triggers a surveillance mechanism that rids the seminiferous tubule of incompetent meiotic cells. In no case was an AE or a SC formed in the mutant spermatocytes, showing that SCP3 indeed constitutes the core. SCP3 was also found to be required for homologous chromosome synapsis, but appears to be dispensable for sister-chromatid cohesion. While the absence of SCP3 affected the nuclear distribution of Rad51, RPA and SCP1, a residual chromatin organisation remained in the mutant meiotic cells. We propose that the sister chromatids are held together by a meiotic cohesin complex functioning as a basic protein backbone. As germ cells enter leptonema, the SC proteins attach to this backbone, forming AEs, and subsequently a synaptonemal complex.

List of scientific papers

I. Yuan L, Liu JG, Hoog C (1995). Rapid cDNA sequencing in combination with RNA expression studies in mice identifies a large number of male germ cell-specific sequence tags. Biol Reprod. 52(1): 131-138.
https://pubmed.ncbi.nlm.nih.gov/95226560

II. Liu JG, Yuan L, Brundell E, Bjorkroth B, Daneholt B, Hoog C (1996). Localization of the N-terminus of SCP1 to the central element of the synaptonemal complex and evidence for direct interactions between the N-termini of SCP1 molecules organized head-to-head. Exp Cell Res. 226(1): 11-19.
https://pubmed.ncbi.nlm.nih.gov/96299545

III. Sage J, Yuan L, Martin L, Mattei MG, Guenet JL, Liu JG, Hoog C, Rassoulzadegan M, Cuzin F (1997). The Sycp1 loci of the mouse genome: successive retropositions of a meiotic gene during the recent evolution of the genus. Genomics. 44(1): 118-126.
https://pubmed.ncbi.nlm.nih.gov/97432827

IV. Yuan L, Pelttari J, Brundell E, Bjorkroth B, Zhao J, Liu JG, Brismar H, Daneholt B, Hoog C (1998). The synaptonemal complex protein SCP3 can form multistranded, cross-striated fibers in vivo. J Cell Biol. 142(2): 331-339.
https://pubmed.ncbi.nlm.nih.gov/98345350

V. Yuan L, Liu JG, Zhao J, Brundell E, Daneholt B, Hoog C (2000). The murine SCP3 gene is required for synaptonemal complex assembly, chromosome synapsis, and male fertility. Mol Cell. 5(1): 73-83.
https://pubmed.ncbi.nlm.nih.gov/20142660