1. Academic Validation
  2. Identifying cross-lineage dependencies of cell-type-specific regulators in mouse gastruloids

Identifying cross-lineage dependencies of cell-type-specific regulators in mouse gastruloids

  • Dev Cell. 2025 Mar 11:S1534-5807(25)00118-2. doi: 10.1016/j.devcel.2025.02.013.
Luca Braccioli 1 Teun van den Brand 2 Noemi Alonso Saiz 2 Charis Fountas 2 Patrick H N Celie 3 Justina Kazokaitė-Adomaitienė 3 Elzo de Wit 4
Affiliations

Affiliations

  • 1 Division of Gene Regulation, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands. Electronic address: l.v.braccioli@uu.nl.
  • 2 Division of Gene Regulation, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
  • 3 Protein Facility, Division of Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Oncode Institute, 3521 AL Utrecht, the Netherlands.
  • 4 Division of Gene Regulation, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands. Electronic address: e.d.wit@nki.nl.
Abstract

Correct gene expression levels are crucial for normal development. Advances in genomics enable the inference of gene regulatory programs active during development but cannot capture the complex multicellular interactions occurring during mammalian embryogenesis in utero. In vitro models of mammalian development, like gastruloids, can overcome this limitation. Using time-resolved single-cell chromatin accessibility analysis, we delineated the regulatory profile during mouse gastruloid development, identifying critical drivers of developmental transitions. Gastruloids develop from bipotent progenitor cells driven by the transcription factors (TFs) OCT4, SOX2, and TBXT, differentiating into the mesoderm (characterized by the mesogenin 1 [MSGN1]) and spinal cord (characterized by CDX2). ΔCDX gastruloids fail to form spinal cord, while Msgn1 ablation inhibits paraxial mesoderm and spinal cord development. Chimeric gastruloids with ΔMSGN1 and wild-type cells formed both tissues, indicating that inter-tissue communication is necessary for spinal cord formation. Our work has important implications for studying inter-tissue communication and gene regulatory programs in development.

Keywords

chromatin accessibility; gastruloid; inter-tissue communication; mesoderm; single-cell ATAC-seq; spinal cord; transcription factor.

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