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

ABSTRACT: The establishment of the left-right axis is crucial 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 crucial 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 southpaw to the left lateral plate mesoderm. Moreover, loss of asymmetric southpaw expression does not result in disturbances to asymmetric organ placement, supporting a model in which 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.

SUBMITTER: Derrick CJ

PROVIDER: S-EPMC9148569 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Pkd1l1 establishes left-right asymmetry and physically interacts with Pkd2.

Project description:In mammals, left-right (L-R) asymmetry is established by posteriorly oriented cilia driving a leftwards laminar flow in the embryonic node, thereby activating asymmetric gene expression. The two-cilia hypothesis argues that immotile cilia detect and respond to this flow through a Pkd2-mediated mechanism; a putative sensory partner protein has, however, remained unidentified. We have identified the Pkd1-related locus Pkd1l1 as a crucial component of L-R patterning in mouse. Systematic comparison of Pkd1l1 and Pkd2 point mutants reveals strong phenocopying, evidenced by both morphological and molecular markers of sidedness; both mutants fail to activate asymmetric gene expression at the node or in the lateral plate and exhibit right isomerism of the lungs. Node and cilia morphology were normal in mutants and cilia demonstrated typical motility, consistent with Pkd1l1 and Pkd2 activity downstream of nodal flow. Cell biological analysis reveals that Pkd1l1 and Pkd2 localise to the cilium and biochemical experiments demonstrate that they can physically interact. Together with co-expression in the node, these data argue that Pkd1l1 is the elusive Pkd2 binding partner required for L-R patterning and support the two-cilia hypothesis.

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Conserved requirement for EGF-CFC genes in vertebrate left-right axis formation.

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Integrated cell-to-cell signaling networks regulate vertebrate axis formation and left-right asymmetry

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Transcriptomic analysis of left-right differences in human embryonic forebrain and midbrain.

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2024-01-08 | PXD032184 | Pride

Fluid-dynamical basis of the embryonic development of left-right asymmetry in vertebrates.

Project description:Experimental work in developmental biology has recently shown in mice that fluid flow driven by rotating cilia in the node, a structure present in the early stages of growth of vertebrate embryos, is responsible for determining the normal development of the left-right axis, with the heart on the left of the body, the liver on the right, and so on. The role of physics, in particular, of fluid dynamics, in the process is one of the important questions that remain to be answered. We show with an analysis of the fluid dynamics of the nodal flow in the developing embryo that the leftward flow that has been experimentally observed may be produced by the monocilia driving it being tilted toward the posterior. We propose a model for morphogen transport and mixing in the nodal flow and discuss how the development of left-right asymmetry might be initiated.

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