NOTCH1 S2513 is critical for the regulation of NICD levels impacting the segmentation clock in hiPSC-derived PSM cells and somitoids

Hedda Meijer (Lead / Corresponding author), Adam Hetherington, Sara Johnson, Rosie L. Gallagher, Izzah N. Hussein, Jess M. Rae, Tomas E.J.C. Noordzij, Margarita Kalamara, Thomas J. Macartney, Lindsay Davidson, David Martin, Paul Davies, Katharina F. Sonnen, Philip Murray, Kim Dale (Lead / Corresponding author)

Research output: Working paper/PreprintPreprint

Abstract

The segmentation clock is a molecular oscillator that regulates the timing of somite formation in the developing vertebrate embryo. NOTCH signalling is one of the key pathways required for proper functioning of the segmentation clock. Aberrant NOTCH signalling results in developmental abnormalities such as congenital scoliosis as well as diseases such as T-cell acute lymphoblastic lymphoma (T-ALL). In this study we analyse the effects of a mutation detected in T-ALL patients on somitogenesis using human iPS derived PSM cells and somitoids. Mutation of NOTCH1 Serine 2513 into Alanine compromises the interaction of Notch intracellular domain (NICD) with the F-box protein FBXW7 and consequently increases NICD stability and NICD levels in PSM cells. Moreover, the mutation impairs several aspects of clock gene oscillations and restricts the ability of somitoids to polarise, elongate and form paired somites. The data suggest a mechanism by which post-translational modification of a key segmentation clock component plays a crucial role in vertebrate axis segmentation.
Original languageEnglish
PublisherBioRxiv
Number of pages38
DOIs
Publication statusPublished - 15 Dec 2024

Keywords

  • NOTCH1
  • segmentation clock
  • somitogenesis
  • hiPSC
  • PSM
  • somitoid

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