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

TY - JOUR

T1 - NOTCH1 S2513 is critical for the regulation of NICD levels impacting the segmentation clock in hiPSC-derived PSM cells and somitoids

AU - Meijer, Hedda

AU - Hetherington, Adam

AU - Johnson, Sara

AU - Gallagher, Rosie L.

AU - Hussein, Izzah N.

AU - Weng, Yuqi

AU - Rae, Jess M.

AU - Noordzij, Tomas E.J.C.

AU - Kalamara, Margarita

AU - Macartney, Thomas J.

AU - Davidson, Lindsay

AU - Martin, David

AU - Gierlinski, Marek

AU - Davies, Paul

AU - Sonnen, Katharina F.

AU - Murray, Philip

AU - Dale, J. Kim

N1 - © 2025 Meijer et al.

PY - 2025/9/1

Y1 - 2025/9/1

N2 - The segmentation clock is a molecular oscillator that regulates the timing of somite formation in the developing vertebrate embryo. NOTCH signaling is one of the key pathways required for proper functioning of the segmentation clock. Aberrant NOTCH signaling 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 analyzed the effects of a mutation detected in T-ALL patients on somitogenesis using human iPSC-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 such as signal intensity, periodicity, directionality of the oscillations, and the ability to sustain oscillations. Furthermore, it restricts the ability of somitoids to polarize, elongate, and form paired segments. The data suggest a mechanism by which post-translational modification of a key segmentation clock component plays a crucial role in vertebrate axis segmentation.

AB - The segmentation clock is a molecular oscillator that regulates the timing of somite formation in the developing vertebrate embryo. NOTCH signaling is one of the key pathways required for proper functioning of the segmentation clock. Aberrant NOTCH signaling 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 analyzed the effects of a mutation detected in T-ALL patients on somitogenesis using human iPSC-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 such as signal intensity, periodicity, directionality of the oscillations, and the ability to sustain oscillations. Furthermore, it restricts the ability of somitoids to polarize, elongate, and form paired segments. The data suggest a mechanism by which post-translational modification of a key segmentation clock component plays a crucial role in vertebrate axis segmentation.

KW - NOTCH1

KW - segmentation clock

KW - somitogenesis

KW - hiPSC

KW - PSM

KW - somitoid

UR - https://www.scopus.com/pages/publications/105015479628

U2 - 10.1101/gad.352909.125

DO - 10.1101/gad.352909.125

M3 - Article

C2 - 40441890

SN - 0890-9369

VL - 39

SP - 1025

EP - 1044

JO - Genes & Development

JF - Genes & Development

IS - 17-18

ER -