Genes Involved in the Germ Line

 

Summary

About 12% of couples are infertile according to the WHO definition. Both partners contribute approximately equally to this. In over half the cases of male infertility the underlying cause is difficult to determine. There are reasons for thinking that genetic causes are at work in over half of these cases but many genes are needed for the production of sperm. The Y chromosome (only present in males) is a favoured place to look for such genes and we are working on a relative of one of these. To spread the net wider we have used micro-array analysis in mice and identified two new genes required for fertility.

 

 

Key Publications

1. Bolcun-Filas, E.; Speed, R.; Taggart, M.; Grey, C.;de Massy, B.; Benavente, R. and Cooke, H.J. Mutation of the Mouse Syce1 Gene Disrupts Synapsis and Suggests a Link Between Synaptonemal Complex Structural Components and DNA Repair. PLoS Genetics 5(2):e1000393, 2009 PubMed Abstract
2. Hamer, G.; Wang, H.; Bolcun-Filas, E.; Cooke, H.J.; Benavente, R. and Hoog, C. Progression of meiotic recombination requires structural maturation of the central element of the synaptonemal complex. J Cell Sci 121:2445-2451, 2008
   PubMed Abstract
3. Ollinger, R.; Childs, A.J.; Burgess, H.M.; Speed, R.M.; Lundegaard, P.R.; Reynolds, N.; Gray, N.K.; Cooke, H.J. and Adams, I.R. Deletion of the pluripotency-associated Tex19.1 gene causes activation of endogenous retroviruses and defective spermatogenesis in mice.
   PLoS Genet 4(9):e1000199, 2008
   PubMed Abstract
4. Bolcun-Filas, E.; Costa, Y.; Speed, R.; Taggart, M.; Benavente, R.; de Rooij, D.G. and Cooke, H.J. SYCE2 is required for synaptonemal complex assembly, double strand break repair, and homologous recombination.
   J Cell Biol 176(6):741-747, 2007
   PubMed Abstract
5. Reynolds, N.; Collier, B.; Bingham, V.; Gray, N.K. and Cooke, H.J. Translation of the synaptonemal complex component Sycp3 is enhanced in vivo by the germ cell specific regulator Dazl. RNA 13(7):974-981, 2007
   PubMed Abstract
6. Costa, Y.; Speed, R.; Gautier, P.; Semple, C.A.; Maratou, K.; Turner, J.M.A. and Cooke, H.J. Mouse MAELSTROM: the link between meiotic silencing of unsynapsed chromatin and microRNA pathway?
   Human Molecular Genetics 15(15):2324-2334, 2006
   PubMed Abstract
7. Collier, B.; Gorgoni, B.; Loveridge, C.; Cooke, H.J. and Gray, N.K. The DAZL family proteins are PABP-binding proteins that regulate translation in germ cells. EMBO J 24(14):2656-2666, 2005 
   PubMed Abstract
8. Costa, Y.; Speed, R.; Ollinger, R.; Alsheimer, M.; Semple, C.A.; Gautier, P.; Maratou, K.; Novak, I.; Hoog, C.; Benavente, R. and Cooke, H.J. Two novel proteins recruited by synaptonemal complex protein 1 (SYCP1) are at the centre of meiosis.
   J Cell Sci 118(Pt 12):2755-2762, 2005 
   PubMed Abstract
9. Reynolds, N. and Cooke, H.J. Role of the DAZ genes in male fertility. Reproductive BioMedicine online 10(1):72-80, 2005 
   PubMed Abstract
10. Reynolds, N.; Collier, B.; Maratou, K.; Bingham, V.; Speed, R.M.; Taggart, M.; Semple, C.A.; Gray, N.K. and Cooke, H.J. Dazl binds in vivo to specific transcripts and can regulate the pre-meiotic translation of Mvh in germ cells.
    Hum Mol Genet 14(24):3899-3909, 2005
    PubMed Abstract
11. Forster, T.; Costa, Y.; Roy, D.; Cooke, H.J. and Maratou, K. Triple-target microarray experiments:a novel experimental strategy.
    BMC Genomics 5:13, 2004 
    PubMed Abstract
12. Maratou, K.; Forster, T.; Costa, Y.; Taggart, M.; Speed, R.M.; Ireland, J.; Teague, P.; Roy, D. and Cooke, H.J. Expression profiling of the developing testis in wild-type and Dazl knockout mice.
    Mol Reprod Dev 67(1):26-54, 2004 
    PubMed Abstract

Collaborations and Funding

Ian Adams
Niki Gray
Richard Meehan
Mary O’Connell
Philippa Saunders
Alan McNeilly
Ricardo Benavente
Christa Heyting
Christer Hoog

 

 

 

Purpose

Gametogenesis is a complex process involving many steps. Some of these are becoming better understood through the use of information from a wide variety of organisms ranging from yeast to flies. Other parts of the process are less well understood and human mutations can be used as entry points to explore novel aspects of the process, to expand the number of individuals who can be diagnosed and ultimately to develop new treatments and contraceptives.

Approach and Progress

We are currently focussing on two aspects of the critical process of meiosis. Generating the haploid gametes from the diploid germ cells must be carried out with extreme accuracy to ensure that the recombination process introduces a minimum of errors and that chromosome segregation is accurate. Systems have to be in place to trap errors and eliminate failing germ cells. Meiosis provides the machinery to do this but the details of this complex process are only beginning to be understood. Meiotic structural proteins are not generally highly conserved at the DNA sequence level although their 3d structures appear to be more conserved. To expand the number of functionally analysed meiotic protein in mammals we have used a micro-array based approach and identified two novel proteins which are essential for the process of synapsis in mouse. These proteins are conserved in mammals and form part of the synaptonemal complex a protein structure containing cohesins and other proteins from which the DNA is looped out. When replicated sister chromatids are tightly aligned a structure called the central element forms. The proteins we identified SYCE1 and SYCE2 are required for the formation of this element with at least two other proteins and if this is not formed then crossover recombination – the basis of all genetics – can not be completed and the germ cells die in both male and females. DNA must traverse the central element at points of crossover and we are linking our mechanistic model of SC formation to the processes of recombination.

 

In the second aspect we have noticed that in a mutant mouse null for the TEX19.1 protein meiosis is perturbed by the mobilisation of a class of retroposon and apparent retention of double strand breaks and aberrant meiotic pairing. We are interested in the mechanisms underlying this process.

 

Future Work

We will continue to investigate the mechanisms by which synaptonemal complexes are assembled and disassembled and their relationship to the enzymology of recombination. We will also focus on the role of transposon mobilisation in the normal process of germ cell development.

 

Transplanted germ cells proliferating in the recipient testis tubules.