Sequential action of JNK genes establishes the embryonic left-right axis

Abstract

The establishment of the left-right axis is critical for the placement, morphogenesis and function of internal organs. Left-right specification is proposed to be dependent on cilia-driven fluid flow in the embryonic node. Planar cell polarity (PCP) signalling is critical for patterning of nodal cilia, yet downstream effectors driving this process remain elusive. We have examined the role of the JNK gene family, a proposed downstream component of PCP signalling, in the development and function of the zebrafish node. We show jnk1 and jnk2 specify length of nodal cilia, generate flow in the node and restrict Nodal to the left lateral plate mesoderm. Moreover, loss of asymmetric Nodal expression does not result in disturbances to asymmetric organ placement, supporting a model that nodal flow may be dispensable for organ laterality. Later, jnk3 is required to restrict pitx2c expression to the left side and permit correct endodermal organ placement. This work uncovers multiple roles for the JNK gene family acting at different points during left-right axis establishment. It highlights extensive redundancy and indicates JNK activity is distinct from the PCP signalling pathway.

JNK regulates ciliogenesis through the interflagellar transport complex and actin networks

“…Recent work shows that JNK acts at different points during left–right axis establishment in zebrafish, distinct from the PCP signaling pathway ( Derrick et al, 2022 ) and regulates nodal cilia length ( Gao et al, 2017 ). Here, we show that loss of JNK in Xenopus MCCs led to serious defects in ciliogenesis, including defective migration and docking of the basal bodies and fewer cilia projecting above the surface of the MCCs.…”

Planar cell polarity regulators in asymmetric organogenesis during development and disease

“…Consistent with their association into a complex, Prickle1 and Prickle2 interact with Vangl2 to regulate its anterior localization in node cells (Minegishi et al, 2017), while Prickle3 shows reciprocal interactions with Vangl2 for the anterior localization in GRP cells to promote growth and posterior positioning of motile cilia (Chu et al, 2016). Downstream of "core" PCP proteins, JNK activity is required for modulating ciliogenesis and cilia length in the zebrafish KV (Derrick et al, 2022). Altogether, these observations reveal an important implication of Wnt/PCP signaling in the orientation of motile cilia within the LRO.…”

Understanding laterality disorders and the left-right organizer: Insights from zebrafish

“…It is interesting to note that mutations in spaw can alter LR asymmetry of the heart (Montague, Gagnon, and Schier 2018) and gut (Noel et al, 2013), but mutations in pitx2 have no such effect on gross heart or gut laterality (Ji, Buel, and Amack 2016). Recently, defects in spaw asymmetry were found to be uncoupled from heart and gut laterality defects in jnk mutants (Derrick et al, 2022). These findings suggest pathways and/or factors in addition to the Nodal-Pitx2 signaling axis can impact heart and gut LR morphogenesis.…”