Professor Kim Dale, Principal Investigator, and her team at the University’s School of Life Sciences have discovered that this mutation can disrupt how segments that later form the bones and muscle of the skeleton are established in early development. When this process goes wrong, it can lead to conditions such as congenital scoliosis – a sideways curvature of the spine.
The mutation occurs in a gene called NOTCH1, which helps control how cells communicate during development. The mutation is already known to appear in many patients with a type of cancer called T-cell acute lymphoblastic leukaemia (T-ALL).
Published in the journal Genes & Development, this new study shows that the same mutation also affects the timing and organisation of the body’s segments. These segments, known as somites, eventually form the spine, muscles, and skeleton.
Using human stem cells and 3D models that mimic early embryos, the Dundee researchers found that the mutation causes a key protein to build up in cells. This interferes with the body’s internal timing system and leads to problems with how somites form.
This is the first time this specific mutation has been shown to interfere with how the basic shape of the human body forms during development.
Dr Hedda Meijer, Senior Postdoctoral Research Assistant who worked on the study, said, “Malfunctioning of somite formation can result in musculoskeletal deformities. A better understanding of the impact of changing the degradation rate of Notch intracellular domain levels on somitogenesis could provide insights into these musculoskeletal deformities, as well as T-cell acute lymphoblastic lymphoma and a variety of other diseases associated with aberrant Notch signalling.”
Along with uncovering this new link, the research also led to the development of specialised lab tools using CRISPR gene editing of stem cell lines. By precisely changing a single letter of the Notch DNA sequence in stem cells, the team was able to mimic the mutation found in patients and observe its effects in early human development.
These CRISPR-edited stem cells can be turned into different types of human cells and tissues, making them a valuable resource for scientists studying the role of Notch in spinal conditions, other developmental tissue contexts where Notch plays a role, and in other diseases linked to faulty NOTCH1 signalling.
The discovery could help researchers understand a wide range of conditions, from musculoskeletal disorders like scoliosis, to cancers involving abnormal cell communication. In the long term, it may also support the development of new ways to diagnose or treat these conditions.
Reference: Meijer HA, Hetherington A, Johnson SJ, et al. NOTCH1 S2513 is critical for the regulation of NICD levels impacting the segmentation clock in hiPSC-derived PSM cells and somitoids. Genes Dev. 2025;39(17-18):1025-1044. doi: 10.1101/gad.352909.125
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