The left-right asymmetry of liver lobation is generated by Pitx2c-mediated asymmetries in the hepatic diverticulum

Abstract

Internal organs exhibit left-right asymmetric sizes, shapes and anatomical positions, but how these different lateralities develop is poorly understood. Here we use the experimentally tractable Xenopus model to uncover the morphogenetic events that drive the left-right asymmetrical lobation of the liver. On the right side of the early hepatic diverticulum, endoderm cells become columnar and apically constricted, forming an expanded epithelial surface and, ultimately, an enlarged right liver lobe. In contrast, the cells on the left side become rounder, and rearrange into a compact, stratified architecture that produces a smaller left lobe. Side-specific gain- and loss-of-function studies reveal that asymmetric expression of the left-right determinant Pitx2c elicits distinct epithelial morphogenesis events in the left side of the diverticulum. Surprisingly, the cellular events induced by Pitx2c during liver development are opposite those induced in other digestive organs, suggesting divergent cellular mechanisms underlie the formation of different lateralities.

The twists and turns of left-right asymmetric gut morphogenesis

“…Consistent with this idea, a recent study in Xenopus showed that, as the early liver diverticulum buds off from the gut tube, hepatic endoderm cells on the right side become more apically constricted, with a greater length-to-width ratio, whereas left-sided cells appear rounder and more compact, indicating that distinct left-and right-sided morphogenetic programs are distinguished very early in liver morphogenesis (Fig. 4A; Womble et al, 2018). In this study, asymmetric expression of pitx2c in the mesoderm surrounding the left side of the early hepatic diverticulum (Fig.…”

“…Furthermore, while the endoderm exhibits cellular-level asymmetries in the developing stomach and liver, no such lateralities have been identified in this tissue layer in the early midgut (Davis et al, 2008). The underlying cellular mechanisms at play in each tissue also vary widely, from LR differences in proliferation to asymmetries in cell shape, polarity, rearrangement and/or ECM remodeling (Davis et al, 2008(Davis et al, , 2017Hecksher-Sørensen et al, 2004;Kurpios et al, 2008;Sivakumar et al, 2018;Welsh et al, 2013;Womble et al, 2018;Fig. 4).…”

“…The action of these cilia generates an asymmetrical fluid flow that establishes local asymmetries in gene expression (Cartwright et al, 2004;Okada et al, 2005;Schweickert et al, 2017;Smith et al, 2008), ultimately leading to the expression of Nodal, a transforming growth factor β superfamily ligand, in the left lateral plate mesoderm (LPM). Nodal then activates expression of the transcription factor Pitx2 in the left LPM and, ultimately, on the left side of developing organs, where it is required for the proper morphogenesis of various anatomical asymmetries (Burn and Hill, 2009;Campione et al, 1999;Davis et al, 2017;Liu et al, 2001;Mahadevan et al, 2014;Muller et al, 2003;Plageman et al, 2011;Ryan et al, 1998;Welsh et al, 2013;Womble et al, 2018). In some species, cilia are not involved and the early symmetry-breaking events remain unclear (Gros et al, 2009;Hamada and Tam, 2020;Kajikawa et al, 2020); nonetheless, the process culminates in LR asymmetrical gene expression in the LPM.…”

Molecular and cellular basis of left–right asymmetry in vertebrates

“…During formation of the liver in Xenopus embryos, endoderm cells on the right side become columnar and apically constricted, whereas those on the left side become rounder and rearrange into a compact structure. 119) The development of such cellular asymmetries is regulated by Pitx2c and is responsible for the generation of future morphological asymmetries of the adult liver. Of interest, the cellular response to Pitx2c in the developing liver is opposite to that apparent in the embryonic midgut, in which endoderm cells on the left side of the dorsal mesentery 158) remain columnar and those on the right side become compact.…”

The Feasibility of Ultrasonographic Diaphragmatic Excursion in Healthy Dogs: Effect of Positioning, Diaphragmatic Location, and Body Weight of Dogs

“…The liver and diaphragm are closely adjacent to each other and the movement of one is reflected in the movement of the other ( 53 ). In dogs, the greatest proportion of the liver lies to the right of the median plane, with a right-to-left proportion of liver of approximately 3:2 ( 55 ) whereas the ratio in humans ranges from 5:1 to 6:1 ( 56 ). Although the detection of DE at the right hemidiaphragm in humans is easier due to a larger window of the liver relative to the splenic window on the left side ( 15 ), DE detection on the left hemidiaphragm could be interrupted by gas in the GI, especially in the stomach.…”