Study of mouse embryos reveals that the specialisation of embryonic cells into germ cells is controlled by a change in tissue organisation – a so-called morphogenetic checkpoint
Credit: Mahmood Shahbazi
A key process in embryo development is the specialisation of cells into either the primordial germ cells, which later give rise to gametes (sperm and eggs), or the cells which make up the rest of the body. Germ cells are crucial as they contain the genetic information which provides links between generations. Exactly why some cells enter the germline to become germ cells, while others do not, has so far been unclear. Marta Shahbazi’s group, in the LMB’s Cell Biology Division, has now identified a new checkpoint mechanism linked to cell morphology which prevents cells from specialising into germ cells.
Spearheaded by Aly Makhlouf, the group studied mouse embryos six days after fertilisation, when primordial germ cells first appear. Observation of these embryos, as well as 3D aggregates grown from mouse embryonic stem cells, revealed the importance of extracellular matrix proteins – proteins which exist outside of cells and usually function as supportive scaffolding for tissues. The group found that germ cells appeared in an area of the embryo which lacked these extracellular matrix proteins.
Manipulation of gene expression in the stem cell aggregates allowed the group to determine the impact of specific compounds and inhibitors on the formation of germ cells. This revealed that when early embryonic cells are in contact with extracellular matrix proteins, they are unable to activate the necessary signals to become germ cells. Therefore, the physical movement of cells away from the extracellular matrix acts as a mechanism to alter the fates of these embryonic cells. This mechanism ensures that only cells in a very specific position within an embryo are able to enter the germline, meaning that germ cells appear at both the right time and place during development.
This research provides new insights into a fundamental aspect of development, revealing how morphological changes impact the process of cell fate specification. It also highlights a previously unappreciated, critical role for the extracellular matrix in regulating entry into the germline. Additionally, a greater understanding of germ cell development is crucial for opening up the possibilities of developing new strategies and interventions to treat infertility, which affects one in six people across the world. Once researchers have determined the molecular mechanisms behind germ cell development in the embryo, it might prove possible to mimic these processes in the lab to make gametes in a dish.
This work was funded by UKRI MRC, European Research Council through UKRI EPSRC, EMBO, Cambridge Trust, the Milstein Fellowship (part of the Max Perutz Fund), the Japan Society for the Promotion of Science (JSPS), and the Medical Research Foundation.
Further references
Integrin signaling in pluripotent cells acts as a gatekeeper of mouse germline entry. Makhlouf, A., Wang, A., Sato, N., Rosa, V.S., Shahbazi, M.N. Science Advances
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As a publicly funded research institute, the LMB is committed to engagement and transparency in all aspects of its research. This research used mice, in accordance with the UK Animals (Scientific Procedures) Act 1986. This work was conducted under a Project Licence, reviewed and approved by the MRC Laboratory of Molecular Biology (LMB) Animal Welfare and Ethical Review Body (AWERB) committee and the UK Home Office.
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