Abstract
c-Jun N-terminal kinase (JNK) is a multi-functional protein involved in a diverse array of context-dependent processes, including apoptosis, cell cycle regulation, adhesion, and differentiation. It is integral to several signalling cascades, notably downstream of non-canonical Wnt and mitogen activated protein kinase (MAPK) signalling pathways. As such, it is a key regulator of cellular behaviour and patterning during embryonic development across the animal kingdom. The cephalochordate amphioxus is an invertebrate chordate model system straddling the invertebrate to vertebrate transition and is thus ideally suited for comparative studies of morphogenesis. However, next to nothing is known about JNK signalling or cellular processes in this lineage. Pharmacological inhibition of JNK signalling using SP600125 during embryonic development arrests gastrula invagination and causes convergence extension-like defects in axial elongation, particularly of the notochord. Pharynx formation and anterior oral mesoderm derivatives like the preoral pit are also affected. This is accompanied by tissue-specific transcriptional changes, including reduced expression of six3/6 and wnt2 in the notochord, and ectopic wnt11 in neurulating embryos treated at late gastrula stages. Cellular delamination results in accumulation of cells in the gut cavity and a dorsal fin-like protrusion, followed by secondary Caspase-3-mediated apoptosis of polarity-deficient cells, a phenotype only partly rescued by co-culture with the pan-Caspase inhibitor Z-VAD-fmk. Ectopic activation of extracellular signal regulated kinase (ERK) signalling in the neighbours of extruded notochord and neural cells, possibly due to altered adhesive and tensile properties, as well as defects in cellular migration, may explain some phenotypes caused by JNK inhibition. Overall, this study supports conserved functions of JNK signalling in mediating the complex balance between cell survival, apoptosis, differentiation, and cell fate specification during cephalochordate morphogenesis.
Highlights
Embryogenesis requires the accurate temporal and spatial coordination of tissue fate, cell movements, and cell numbers in a controlled and reproducible way
We propose that an appropriate balance of Jun N-terminal kinase (JNK) signalling is required to maintain cellular integrity and polarity, and that mis-regulation results in cells delaminating through changes in the actin cytoskeleton and phosphorylated extracellular signal regulated kinase (ERK), culminating in Caspase-mediated cell death of depolarised cells
JNK Plays a Role in Invagination and Elongation in Amphioxus In Drosophila, there is a single JNK orthologue, but in humans, there are three JNK genes (JNK1, 2, and 3 or mitogen activated protein kinase (MAPK) 8, 9, and 10) resulting from the two whole genome duplications in the ancestor of the vertebrate lineage (Dehal and Boore, 2005)
Summary
Embryogenesis requires the accurate temporal and spatial coordination of tissue fate, cell movements, and cell numbers in a controlled and reproducible way In most metazoans, this is achieved by the complex orchestration of only seven evolutionarily conserved developmental pathways, including canonical Wnt, JAK/STAT, TGFb, Hh, Nuclear Receptor, Notch/Delta, and receptor tyrosine kinase (RTK) signalling (Babonis and Martindale, 2017). This is achieved by the complex orchestration of only seven evolutionarily conserved developmental pathways, including canonical Wnt, JAK/STAT, TGFb, Hh, Nuclear Receptor, Notch/Delta, and receptor tyrosine kinase (RTK) signalling (Babonis and Martindale, 2017) Small changes in this equilibrium can either result in a complete failure of development, with the generation of “monsters,” or, if increasing fitness over evolutionary time, in the diversity of organismal form and function seen today. JNK regulates apoptosis and the cell cycle (Pinal et al, 2019), and, to p38 (Canovas and Nebreda, 2021), some stress responses
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