Conserved signals control self-organization and symmetry breaking of murine bilayered epithelia during development and regeneration

  • Dev Cell. 2025 Jun 25:S1534-5807(25)00362-4. doi: 10.1016/j.devcel.2025.06.007.
Robin P Journot  1 ,  Mathilde Huyghe  2 ,  Alexandre Barthelemy  2 ,  Hugo Couto-Moreira  2 ,  Tom Deshayes  2 ,  Louise Harari  2 ,  Jakub Sumbal  3 ,  Marisa M Faraldo  2 ,  Maxime Dubail  4 ,  Charles Fouillade  4 ,  Silvia Fre  5
Affiliations
  • 1. Institut Curie, PSL University, Sorbonne Université, CNRS UMR3215, Inserm U934, Genetics and Developmental Biology, 75005 Paris, France. Electronic address: [email protected].
  • 2. Institut Curie, PSL University, Sorbonne Université, CNRS UMR3215, Inserm U934, Genetics and Developmental Biology, 75005 Paris, France.
  • 3. Institut Curie, PSL University, Sorbonne Université, CNRS UMR3215, Inserm U934, Genetics and Developmental Biology, 75005 Paris, France; Masaryk University, Faculty of Medicine, Department of Histology and Embryology, Kamenice 3, Brno 625 00, Czech Republic.
  • 4. Institut Curie, Inserm U1021, CNRS UMR 3347, Paris Saclay University, Centre Universitaire, 91405 Orsay Cedex, France.
  • 5. Institut Curie, PSL University, Sorbonne Université, CNRS UMR3215, Inserm U934, Genetics and Developmental Biology, 75005 Paris, France. Electronic address: [email protected].
PMID: 40592344 DOI: 10.1016/j.devcel.2025.06.007
Abstract

Organ development relies on molecular cues that guide stem cells to differentiate within precise spatial arrangements. After injury, restoring these patterns is key for regeneration. Yet, how tissue geometry shapes cell fate remains unclear. This study employs a comprehensive approach using in vitro organoids, ex vivo embryonic tissue explants, and single-cell quantitative imaging to investigate cell fate acquisition in four murine bilayered epithelia during development and regeneration. The findings identify that tissue architecture serves as the primary driver of cell fate decisions, with symmetry breaking initiated during early cell internalization. Genetic and pharmacological analyses demonstrate that Hippo/YAP and Notch signaling pathways coordinate to link tissue structure with differentiation outcomes. This study identifies the inherent capacity of stem cells to self-organize into multicellular structures, where the precise position of each differentiated cell is critical to instruct their differentiation choices during embryonic development and regeneration.

Keywords
Hippo pathway; Notch pathway; binary fate decisions; epithelial stem cells; glandular epithelia; lateral inhibition; pattern establishment; regeneration; self-organization; symmetry breaking.
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