For both titles please look in the abstract session below.

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• Katie Goodwin-MRC LMB; Miguel Ángel Ortiz Salazar-MRC LMB
• Monday 19 May 2025, 14:30-15:30
• In person at Gurdon Institute and Online.

If you have a question about this talk, please contact Jia CHEN.

Katie Goodwin Title: Physical confinement in the developing mouse embryo puts migrating primordial germ cells at risk of DNA damage

Abstract: High fidelity passing on of genetic material is essential to reproduction. Typically, this is accomplished by primordial germ cells (PGCs), which eventually produce sperm or eggs. In most animals, PGCs are specified far from the future gonads and must migrate through developing tissues to reach them. Failure to complete this journey can result in infertility or extra-gonadal germ cell tumours. Despite this important biomedical relevance, very little is known about PGC migration in mammalian embryos. Here, we performed dynamic and in-depth analyses of PGC migration during mouse embryogenesis, encompassing historically inaccessible stages. We found that migrating PGCs extend dynamic actin-rich protrusions, indicative of a migration strategy distinct to that used in non-mammalian model organisms. Their protrusive migration enables them to navigate through ECM barriers and increasingly developed tissues. These morphogenetic changes around PGCs impose increasing physical confinement, leading to significant nuclear deformation and even cell rupture. Endogenous and artificial increases in confinement lead to an increased incidence of DNA damage in PGCs, but not somatic cells. As a possible adaptation to mitigate this surprising stress, we found that PGCs deplete their nuclear lamina and have highly wrinkled nuclear envelopes that may enable them to squeeze through confined spaces damage-free. Overall, our insights into the fascinating journey of PGCs during mouse embryogenesis raise important questions about DNA repair, nuclear adaptations, and genome integrity in the mammalian germline.

Miguel Ángel Ortiz Salazar Title: Endogenous Nodal diverts Wnt signaling interpretation from posterior mesoderm to definitive endoderm in geometrically constrained human pluripotent cells.

Abstract: The ligands FGF8 and WNT3A are crucial for embryonic development. They are involved in cell migration, aid mesoderm induction early at gastrulation, and fuel axial elongation by generating Neuromesodermal progenitors (NMPs) that pattern posterior cell fates in the embryo. While both events have been extensively studied, the mechanisms by which these signals produce different outcomes depending on the context remain elusive. Here, we studied how the Wnt signaling dynamics correlate with their cell fate.

When human embryonic stem cells are exposed to these signals under standard culture conditions, they indeed induce an NMP -like state. In contrast, however, when the same protocol is performed in geometrically constrained colonies, an intricate 3D structure emerges, featuring a ball of epiblast disk-like cells (SOX2+, OCT4 , NANOG , ECAD ) on top of layers of definitive endoderm (DE) (SOX17, FOXA2 , GATA6 , NCAD , OTX2 ). When these structures are exposed to increasing WNT doses, signaling levels as measured with live GFP ::ß-catenin are elevated. However, these elevated WNT signals do not induce mesoderm or posteriorize the responding cells, challenging the classic concentration-dependent morphogen mechanism. By manipulating signaling pathways, we found that DE differentiation results from elevated endogenous NODAL signaling together with the exogenous WNT stimulation. The ability of WNT to induce NMPs and their specialized descendants, pre-somitic mesoderm (PSM) or neural progenitors (CDX1+, CDX2 , and TBX6 or SOX1 , SOX2 ) is restored only when WNT activation is combined with NODAL inhibition. Furthermore, combining live NODAL dynamics with time-point inhibitions, revealed that allowing NODAL signaling for the first 24 hours, enhances PSM induction while allowing it for 48 hours induces both DE and PSM fates. This shows that NODAL changes how the WNT signal is interpreted and is the main determinant of whether cells differentiate to endoderm or mesoderm. Finally, we determined that CHIR , a commonly used chemical Wnt activator, can induce PSM in a concentration-dependent manner with qualitatively different signaling dynamics through both the WNT and NODAL pathways compared to stimulation with WNT3A ligand.

Collectively, we demonstrate that cell fate decision-making is determined by the interplay between multiple pathways and not only by the levels of a single pathway, highlighting the dynamic nature of development.

This work has been funded by the National Science Foundation (MCB-2135296), Rice University, and Consejo Nacional de Ciencia y Tecnología (CONACYT – 41944)

This talk is part of the Morphogenesis Seminar Series series.

This talk is included in these lists:

• Graduate-Seminars
• In person at Gurdon Institute and Online
• Morphogenesis Seminar Series
• Venue to be confirmed

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