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SUMMARY:For both titles please look in the abstract session below. - Katie
  Goodwin-MRC LMB\; Miguel Ángel Ortiz Salazar-MRC LMB
DTSTART:20250519T133000Z
DTEND:20250519T143000Z
UID:TALK230878@talks.cam.ac.uk
CONTACT:Jia CHEN
DESCRIPTION:Katie Goodwin \nTitle: Physical confinement in the developing 
 mouse embryo puts migrating primordial germ cells at risk of DNA damage \n
  \nAbstract: High fidelity passing on of genetic material is essential to 
 reproduction. Typically\, this is accomplished by primordial germ cells (P
 GCs)\, which eventually produce sperm or eggs. In most animals\, PGCs are 
 specified far from the future gonads and must migrate through developing t
 issues to reach them. Failure to complete this journey can result in infer
 tility or extra-gonadal germ cell tumours. Despite this important biomedic
 al relevance\, very little is known about PGC migration in mammalian embry
 os. Here\, we performed dynamic and in-depth analyses of PGC migration dur
 ing mouse embryogenesis\, encompassing historically inaccessible stages. W
 e found that migrating PGCs extend dynamic actin-rich protrusions\, indica
 tive 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 significan
 t nuclear deformation and even cell rupture. Endogenous and artificial inc
 reases in confinement lead to an increased incidence of DNA damage in PGCs
 \, but not somatic cells. As a possible adaptation to mitigate this surpri
 sing stress\, we found that PGCs deplete their nuclear lamina and have hig
 hly wrinkled nuclear envelopes that may enable them to squeeze through con
 fined spaces damage-free. Overall\, our insights into the fascinating jour
 ney of PGCs during mouse embryogenesis raise important questions about DNA
  repair\, nuclear adaptations\, and genome integrity in the mammalian germ
 line. \n\nMiguel Ángel Ortiz Salazar\nTitle: Endogenous Nodal diverts Wnt
  signaling interpretation from posterior mesoderm to definitive endoderm i
 n geometrically constrained human pluripotent cells. \n\nAbstract: The lig
 ands FGF8 and WNT3A are crucial for embryonic development. They are involv
 ed in cell migration\, aid mesoderm induction early at gastrulation\, and 
 fuel axial elongation by generating Neuromesodermal progenitors (NMPs) tha
 t pattern posterior cell fates in the embryo. While both events have been 
 extensively studied\, the mechanisms by which these  signals produce diffe
 rent outcomes depending on the context remain elusive. Here\, we studied h
 ow the Wnt signaling dynamics correlate with their cell fate.  \n\nWhen hu
 man embryonic stem cells are exposed to these signals under standard cultu
 re conditions\, they indeed induce an NMP-like state. In contrast\, howeve
 r\, when the same protocol is performed in geometrically constrained colon
 ies\, an intricate 3D structure emerges\, featuring a ball of epiblast dis
 k-like cells (SOX2+\, OCT4+\, NANOG+\, ECAD+) on top of layers of definiti
 ve endoderm (DE) (SOX17+\, FOXA2+\, GATA6+\, NCAD+\, OTX2+). When these st
 ructures are exposed to increasing WNT doses\, signaling levels as measure
 d with live GFP::ß-catenin are elevated. However\, these elevated WNT sig
 nals do not induce mesoderm or posteriorize the responding cells\, challen
 ging the classic concentration-dependent morphogen mechanism. By manipulat
 ing signaling pathways\, we found that DE differentiation results from ele
 vated endogenous NODAL signaling together with the exogenous WNT stimulati
 on. 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-po
 int 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 int
 erpreted and is the main determinant of whether cells differentiate to end
 oderm or mesoderm. Finally\, we determined that CHIR\, a commonly used che
 mical Wnt activator\, can induce PSM in a concentration-dependent manner w
 ith qualitatively different signaling dynamics through both the WNT and NO
 DAL pathways compared to stimulation with WNT3A ligand. \n\nCollectively\,
  we demonstrate that cell fate decision-making is determined by the interp
 lay between multiple pathways and not only by the levels of a single pathw
 ay\, highlighting the dynamic nature of development. \n\nThis work has bee
 n funded by the National Science Foundation (MCB-2135296)\, Rice Universit
 y\, and Consejo Nacional de Ciencia y Tecnología (CONACYT - 41944)
LOCATION:In person at Gurdon Institute and Online
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