Germline and Pluripotency

“Our overarching goal is to study development to improve the understanding of human disease”

Germ cells contain all of the information required to build a new embryo, including the parental genomes which are modified and regulated by epigenetic factors. We are interested in how the germline is established during primordial germ cell (PGC) development, and how this goes wrong leading to either infertility or germ cell tumours (GCTs). Our interests extend to the next generation, where we study the earliest stages of embryonic development. Pluripotency, defined as the capacity of a single cell to form all adult cell lineages, is a key theme in our research. Pluripotency must be regulated in the germline to prevent tumorigenesis and be properly established in vivo and in vitro to allow appropriate differentiation.

We use mouse models to analyse and manipulate PGCs in the embryo in vivo, and have established novel conditions to investigate the properties of mouse PGCs in vitro. In particular, we study how pluripotency is regulated in PGCs, how developmental signals regulate epigenetic reprogramming, and the molecular mechanism of PGC migration. Dysregulation of these processes are likely key to the pathogenesis of paediatric GCTs, 50% of which occur outside the gonad. We also study these same processes in human pluripotent stem cell models of PGC development and in ex vivo human germ cells. We hypothesise that defects in PGC development may lead to severe forms of human infertility, and so we are using trio exome sequencing of infertile men to identify causative gene variants and pluripotent stem cell models to establish if these variants lead to defects in PGC development. Thus, we aim to identify new players in human germline development and improve the diagnosis and future treatment of severe infertility.

More broadly, we study how signalling molecules, transcription factors and epigenetic modifications combine to correctly regulate pluripotency in mouse and human stem cells. Such information will be key to allow accurate modelling of human development and disease. Indeed, we have a particular interest in using human pluripotent stem cell models to functionally validate genetic variants identified in severely unwell neonates with a likely underlying genetic disorder, and to model these genetic disorders in vitro using organoid technology.

Germline and Pluripotency

Selected References

Hamazaki N, Kyogoku H, Araki H, Miura F, Horikawa C, Hamada N, Shimamoto S, Hikabe O, Nakashima K, Kitajima T, Ito T, Leitch HG, Hayashi K. (2021). Reconstitution of the oocyte transcriptional network with transcription factors. Nature 286, 493–6.

Posfai E, Lanner F, Mulas C, Leitch HG. (2021). All models are wrong, but some are useful: Establishing standards for stem cell-based embryo models. Stem Cell Reports 16(5), 1117-1141.

Mulas C, Kalkan T, von Meyenn F, Leitch HG, Nichols J, Smith A. (2019). Defined conditions for propagation and manipulation of mouse embryonic stem cells. Development 146(6).

Cvetesic N, Leitch HG, Borkowska M, Müller F, Carninci P, Hajkova P, Lenhard B. (2018). SLIC-CAGE: high-resolution transcription start site mapping using nanogram-levels of total RNA. Genome Research 28(12), 1943–1956.

Hill PWS, Leitch HG, Sun Z, Requena-Torres C, Amouroux R, Trufero M, Borkowska M, Terragni J, Vaisvila R, Linnett S, Dharmalingham G, Haberle V, Lenhard B, Zheng Y, Pradhan S, Hajkova P (2018). Epigenetic reprogramming enables the primordial germ cell-to-gonocyte transition in mouse. Nature 555(7696), 392–396.

Zhang M, Leitch HG, Tang WWC, Festuccia N, Hall-Ponsele E, Nichols J, Surani MA, Smith A, Chambers I. (2018). Esrrb Complementation Rescues Development of Nanog-Null Germ Cells. Cell Reports 22(2), 332-339.

De Los Angeles A, Ferrari F, Xi R, Fujiwara Y, Benvenisty N, Deng H, Hochedlinger K, Jaenisch R, Lee S, Leitch HG, Lensch MW, Lujan E, Pei D, Rossant J, Wernig M, Park PJ, Daley GQ. (2015). Hallmarks of PluripotencyNature 525(7570), 469-78.

Leitch HG, Okamura D, Durcova-Hills G, Stewart CL, Gardner RL, Matsui Y, Papaioannou VE.(2014). On the fate of primordial germ cells injected into early mouse embryos. Developmental Biology 385(2), 155-9.

Leitch HG, Nichols J, Humphreys P, Mulas C, Martello G, Lee C, Jones K, Surani MA, Smith A. (2013). Rebuilding pluripotency from primordial germ cells. Stem Cell Reports 1(1), 66-78.

Leitch HG, McEwen KR, Turp A, Encheva V, Carroll T, Grabole N, Mansfield W, Nashun B, Knezovich JG, Smith A, Surani MA, Hajkova P. (2013). Naïve pluripotency is associated with global DNA hypomethylation. Nature Structural & Molecular Biology 20(3), 311–316