Agnes Katharina Ulfig and Hans Tómas Björnsson
Introduction. Kabuki syndrome type 1 (KS1) is a genetic disorder caused by mutations in KMT2D. Individuals with KS1 exhibit distinct facial features and congenital anomalies, including heart defects and skeletal abnormalities. Importantly, the affected tissues are primarily formed by the neural crest (NC), a multipotent migratory cell population in the developing embryo. Defects in NC cells (NCCs) result in a range of craniofacial birth defects and disorders known as neurocristopathies. Intriguingly, in several neurocristopathies, disruption in NC development has been mechanistically linked to hyperactivation of the cellular stress sensor p53. Considering the spectrum of phenotypes in KS1 resembling a classical neurocristopathy and our previous finding that embryogenesis in KS1 occurs under elevated oxidative stress, we now suspect that the developmental defects might be caused by redox imbalance which leads to p53 activation and dysregulation of NC development.
Methods. We differentiated wild-type and Kmt2d-deficient mouse embryonic stem cells into migratory NCCs and compared their (1) migration capacity and expression of epithelial-to-mesenchymal transition (EMT)-related genes by quantitative PCR, (2) mitochondrial activity using fluorescent probes and Seahorse assays, and (3) p53 levels by Western blotting.
Results. Kmt2d-deficient NCCs exhibited migration defects, mitochondrial stress and higher p53 levels.
Conclusions. These preliminary experiments using a cellular KS1 model confirmed impaired NC development and provided first evidence that increased oxidative stress might be the underlying cause. Hence, maintaining redox balance during development could be an effective strategy to prevent KS1-associated developmental defects. We will now validate our findings in vivo using a mouse model of KS1.
