Cilia in vertebrate left–right patterning

Abstract

One contribution of 17 to a theme issue 'Provocative questions in left -right asymmetry'. Understanding how left-right (LR) asymmetry is generated in vertebrate embryos is an important problem in developmental biology. In humans, a failure to align the left and right sides of cardiovascular and/or gastrointestinal systems often results in birth defects. Evidence from patients and animal models has implicated cilia in the process of left-right patterning. Here, we review the proposed functions for cilia in establishing LR asymmetry, which include creating transient leftward fluid flows in an embryonic 'left -right organizer'. These flows direct asymmetric activation of a conserved Nodal (TGFb) signalling pathway that guides asymmetric morphogenesis of developing organs. We discuss the leading hypotheses for how cilia-generated asymmetric fluid flows are translated into asymmetric molecular signals. We also discuss emerging mechanisms that control the subcellular positioning of cilia and the cellular architecture of the left-right organizer, both of which are critical for effective cilia function during left-right patterning. Finally, using mosaic cell-labelling and timelapse imaging in the zebrafish embryo, we provide new evidence that precursor cells maintain their relative positions as they give rise to the ciliated left -right organizer. This suggests the possibility that these cells acquire left-right positional information prior to the appearance of cilia.This article is part of the themed issue 'Provocative questions in leftright asymmetry'.

Genes and molecular pathways underpinning ciliopathies

“…Other motile cilia do not propel cells but instead move the overlying fluid. Such cilia are found on airway epithelial cells, oviduct cells, ependymal cells that line the brain ventricles, and on the node, which is a transient developmental structure that is crucial for left–right axis determination 21 .…”

Left–Right Patterning: Breaking Symmetry to Asymmetric Morphogenesis

“…Though LROs are structurally diverse [5], the logic of how L-R symmetry is broken within them appears to be conserved across many vertebrates [6]. Cilia, microtubule-based organelles that protrude from the apical surface of cells, are found within LROs, one cilium per cell [7]. These cilia rotate and, as a result, generate fluid flow within the cavity of the LRO which is L-R asymmetric (Figure 1A) (Box 1).…”

The Many Sides of Hemispheric Asymmetry: A Selective Review and Outlook

“…The asymmetries of the internal organs are governed at the earliest stages by an asymmetry of the cilia, asymmetrical hair-like organelles on the surface of cells, and this directs the asymmetry of a genetic sequence (the Nodal-Lefty-Pitx2 cascade), which guides the asymmetrical morphogenesis of internal organs through a cascade of genetic influences (Dasgupta & Amack, 2016). One gene in this complex is the PCSK6 gene, which activates Nodal, and a genome-wide assay across three independent samples of individuals with dyslexia showed one allele of PCSK6 to be significantly associated with increased right-handedness (Scerri et al, 2011).…”