Coordination of the chromosomal events of meiosis in C. elegans and rice

Lead Research Organisation: Imperial College London
Department Name: Institute of Clinical Sciences

Abstract

DNA is the molecule that holds the information to control biological processes in living organisms. DNA is like a book that contains the blueprints to build an organism. As a book is organised into chapters, DNA is divided into individual structures called chromosomes. Human DNA is divided into 23 chromosomes, each one carrying the genetic information needed for specific processes. It is crucial that this information is passed on accurately when organisms reproduce. Humans, as most animals and plants, reproduce sexually by the fusion of two gametes (sperm and egg) to form an embryo. Gametes carry one copy of each chromosome, so their fusion results in an embryo carrying two copies of each chromosome (known as homologues), one copy from dad and another from mum. Homologues are separated during gamete formation by a specialised cell division known as meiosis. Defects in meiosis result in gametes with the wrong number of chromosomes; causing miscarriages and birth defects. For example, Down Syndrome is caused by the presence of an extra chromosome 21. Despite the importance of meiosis we still do not understand how this complicated process works. Before entering meiosis, homologues are separate from each other inside a specific compartment of the cell called the nucleus. At the start of meiosis a remarkable process takes place in which homologues are able to recognise each other among all the chromosomes present in the nucleus. By the end of this phase, homologous chromosomes are completely aligned and a protein scaffold, known as the synaptonemal complex (SC), is loaded in between them. In this context, fragments of DNA are interchanged between the paternal and maternal copies of each chromosome pair. This DNA interchange is known as genetic recombination, it provides a stable physical link between the homologues that ultimately allows them to segregate away from each other to produce cells that carry a single copy of each chromosome. My research aims to understand the mechanisms that ensure proper homologous chromosome separation during meiosis. I am using a worm, C. elegans, as an experimental system. In these tiny worms more than 50% of the cells in the adults are undergoing meiosis. During my current research I found a protein, HTP-1, which plays a crucial role in ensuring that only homologous chromosomes are glued together by the SC, avoiding connections between unrelated chromosomes. This research showed that homologue pairing and SC assembly are coordinated by complex monitoring mechanisms. Finding new proteins involved in these mechanisms is crucial to understand how chromosomes choose their correct pairing partner: 1/ I will find these proteins by looking for proteins that physically interact during meiosis with HTP-1. 2/ I will carry out different genetic screens to isolate new worm mutants that display meiotic defects similar to those observed in worms lacking the HTP-1 protein. High-resolution microscopy will be used to investigate the role of the newly found proteins during homologue pairing. I will extend my studies of meiosis to rice, a plant that serves as a model organism for the most economically important group of plants, the cereals. I will start by analysing, how different regions of homologous chromosomes change their structure as they pair. Using an assay that isolates proteins based on their interaction with known proteins, I will find proteins that play roles in the processes of homologue pairing, SC assembly and recombination. Finally, I will investigate how homologous chromosomes behave during meiosis in two rice lines that lack proteins needed for the process of genetic recombination. In some organisms the processes of homologue pairing and recombination are intrinsically coupled, I will determine if this is the case in rice.

Technical Summary

Chromosome partitioning during meiosis is achieved by a complex series of events that includes DNA replication, alignment and pairing of homologous chromosomes, stabilisation of pairing by the synaptonemal complex (SC) and creation of physical links (crossovers) between the homologues. Crossovers ultimately direct chromosomes to segregate from each other. Despite the importance of meiosis, the molecular mechanisms underlying these events remain largely mysterious. I will investigate these events in the nematode C. elegans and in rice, two experimental organisms that offer unique advantages for the study of meiosis. Homologue pairing coincides with a reorganisation of chromatin within the nucleus. My previous research identified two checkpoint-like mechanisms that operate during early prophase to coordinate pairing with SC assembly and nuclear reorganisation. These mechanisms ensure that SC is only assembled between correctly paired homologues; favouring recombination between the homologues. I will use a combined experimental approach that includes genetics, biochemistry and high-resolution microscopy to identify and investigate the function of new components of these coordinating mechanisms. The importance of cytoskeleton components for nuclear reorganisation and homologue pairing will also be tested. Further, I will investigate a possible connection between the regulation of premeiotic S-phase and meiotic prophase chromosome metabolism. Studies will be also directed towards rice, an excellent model for the most important group of cultivated plants, the cereals. A biochemical approach will be used to identify proteins involved in specific meiotic processes and the role of these proteins will be investigated using post-transcriptional gene silencing of the corresponding genes. Genetic analysis of rice will commence by investigating the role of conserved recombination genes. The rice system holds great promise as a model for investigating meiosis in monocots.

Related Projects

Project Reference Relationship Related To Start End Award Value
BB/D020336/1 02/10/2006 01/09/2009 £667,755
BB/D020336/2 Transfer BB/D020336/1 01/09/2009 30/11/2011 £254,196
 
Description How specific proteins contribute to ensure that sperm and eggs receive the correct number of chromosomes. This is essential for fertility and to prevent developmental associated with incorrect chromosome numbers, such as Down's syndrome.
Exploitation Route We have uncovered how conserved HORMA domain proteins contribute to chromosome segregation during meiosis. These findings provide the basis for future studies aiming to elucidate how to prevent the formation of aneuploid gametes.
Sectors Pharmaceuticals and Medical Biotechnology