JNK Mediates Differentiation, Cell Polarity and Apoptosis During Amphioxus Development by Regulating Actin Cytoskeleton Dynamics and ERK Signalling

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.

N-linked glycosylation is essential for anti-tumor activities of KIAA1324 in gastric cancer

“…8A). In this study, we demonstrated that JNK signaling, a well-known apoptotic signaling [35][36][37], was involved in KIAA1324-mediated apoptosis (Fig. 4B).…”

“…4A). Since JNK is known to be an apoptosis regulator [35][36][37], the IPA network 1 represents that the up-regulated transcription program by N-glycosylated KIAA1324 is associated with apoptosis via JNK protein. The IPA network 2 includes many down-regulated genes and E2F1 a hub protein, which is consistent with the GRN analysis result (Supplementary Fig.…”

N-linked glycosylation is essential for anti-tumor activities of KIAA1324 in gastric cancer

“…4A, B). In this study, we demonstrated that JNK signaling, a well-known apoptotic signaling (32,33,34), was involved in KIAA1324-mediated apoptosis (Supplementary Fig. 5).…”

“…4A). Since JNK is known to be an apoptosis regulator (32,33,34), the IPA network 1 represents that the upregulated transcription program by N-glycosylated KIAA1324 is associated with apoptosis via JNK protein. The IPA network 2 includes many down-regulated genes and E2F1 a hub protein (Fig.…”