Mouse Germ Cell Development

Lead Research Organisation: MRC Human Genetics Unit

Abstract

We are interested in how germ cells decide whether to become male sperm or female eggs during development of the mouse embryo.||An embryos decision to become male or female is based on the sex chromosomes that it inherits from its parents. However the sex chromosomes do not act directly on the germ cells, rather the sex chromosomes act in the supporting cells that surround and nurture the germ cells. These supporting cells then generate unknown signals that tell the germ cells to become male or female. We are interested in what these signals are, and how the germ cells respond to them.||We are using molecular tools to identify sex-specific genes in the developing germ cells. We then use cell culture, organ culture, and finally genetically modified mice to investigate how these genes act on the germ cells decision to become male or female.||If germ cells get the decision to become male or female wrong, then this can lead to testicular cancer, the most common cancer present in young men.||We hope that this research will discover how germ cells make this fundamental decision and, in the longer term, will provide insight into the origins of testicular cancer.

Technical Summary

Germ cells play a central role in genetics and inheritance to transmit genetic information from one generation to the next. However the way in which the germ cells do this differs between males and females. Differences between germ cell behaviour in male and female embryonic gonads are caused by sex-determining cues in the embryonic gonadal environment rather than by the intrinsic sex chromosome constitution of the germ cells themselves. The aim of this research programme is to identify the molecular nature of these signals, and how the germ cells respond to them.||We have identified an evolutionally conserved transmembrane protein, Sdmg1 that is expressed in the Sertoli cells of male embryonic gonads at the time of germ cell sex determination. In adult mice, Sdmg1 is associated with specialised secretory granules in secretory exocrine cells suggesting that this protein may have a role in membrane trafficking. RNAi-mediated knock-down of Sdmg1 in conditionally immortalised Sertoli cell lines results in perturbed membrane trafficking and impaired masculinisation of germ cells in organ culture, and RNAi-mediated knock-down of Sdmg1 in mouse embryos causes defects in germ cell masculinisation. This suggests that Sdmg1 mediates secretion of germ cell masculinising factors from the Sertoli cells. We aim to extend this work by attempting to identify molecules that require Sdmg1 for their secretion from Sertoli cells. We have also generated and are characterising Sdmg1 knockout mice.||One of the consequences of the germ cells sex determining decision for human genetics is that male and female germ cells tend to transmit different types of de novo mutations to the next generation. We have identified a novel genetic pathway operating in male and female mouse germ cells that helps maintain genetic and chromosomal stability through successive generations. We are currently investigating how this novel pathway operates, and whether it might contribute to the high rates of aneuploidy that arise during oogenesis in humans.

Publications

10 25 50
 
Title Microarray repeat annotation 
Description Bioinformatic approach to analyse repetitive element expression from microarray data 
Type Of Material Improvements to research infrastructure 
Year Produced 2012 
Provided To Others? Yes  
Impact PMID: 22570599 
URL http://europepmc.org/abstract/MED/22570599
 
Title Tex19.1 knockout mice 
Description Tex19.1 knockout mice, model for aneuploidy 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2008 
Provided To Others? Yes  
Impact Publication - PMID: 18802469 
URL http://europepmc.org/abstract/MED/18802469
 
Description Andrew Peden 
Organisation University of Cambridge
Department Cambridge Institute for Medical Research (CIMR)
Country United Kingdom 
Sector Academic/University 
PI Contribution Designed study, performed experiments
Collaborator Contribution Provided reagents, performed experiments, generated data
Impact Publication PMID: 18321981
Start Year 2006
 
Description Gabriela Durcova-Hills 
Organisation University of Cambridge
Department Gurdon Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Provided reagents
Collaborator Contribution Designed and performed experiments
Impact PMID: 16769760
 
Description Marie-Christine Chaboissier 
Organisation University of Paris-Est
Department UMR 636 (Genetics of normal and pathological development)
Country France 
Sector Academic/University 
PI Contribution Contributed reagents and expertise to study
Collaborator Contribution Co-publication
Impact Publication PMID:21991325
Start Year 2008
 
Description Niki Gray 
Organisation Medical Research Council (MRC)
Department MRC Human Reproductive Sciences Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution Designed study, performed experiments
Collaborator Contribution Performed experiments
Impact PMID: 18802469
Start Year 2008
 
Description Norbert Walther 
Organisation Friedrich-Alexander University Erlangen-Nuremberg
Department School of Life Sciences Friedrich-Alexander
Country Germany 
Sector Academic/University 
PI Contribution Designed study, performed experiments
Collaborator Contribution Provided reagents
Impact Publication PMID: 18321981
Start Year 2006
 
Description Rasmus Hartmann-Petersen 
Organisation University of Copenhagen
Department Department of Biology
Country Denmark 
Sector Academic/University 
PI Contribution Provided experimental data for publication
Collaborator Contribution Co-publication
Impact Co-publication PMID:21949850
Start Year 2010