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Mechanical regulation of early vertebrate embryogenesis

Abstract

Embryonic cells grow in environments that provide a plethora of physical cues, including mechanical forces that shape the development of the entire embryo. Despite their prevalence, the role of these forces in embryonic development and their integration with chemical signals have been mostly neglected, and scrutiny in modern molecular embryology tilted, instead, towards the dissection of molecular pathways involved in cell fate determination and patterning. It is now possible to investigate how mechanical signals induce downstream genetic regulatory networks to regulate key developmental processes in the embryo. Here, we review the insights into mechanical control of early vertebrate development, including the role of forces in tissue patterning and embryonic axis formation. We also highlight recent in vitro approaches using individual embryonic stem cells and self-organizing multicellular models of human embryos, which have been instrumental in expanding our understanding of how mechanics tune cell fate and cellular rearrangements during human embryonic development.

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Fig. 1: Forces acting in animal embryos.
Fig. 2: Mechanical regulation of cell fate.
Fig. 3: Force-induced symmetry breaking.
Fig. 4: Mechanics of cell rearrangements.
Fig. 5: Stem cell models of early mammalian development.
Fig. 6: Human gastruloids.

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Acknowledgements

The authors thank all members of the Brivanlou laboratory, C. LaBonne, O. Campàs and participants in the 2021 Marine Biological Laboratory (MBL) Embryology Advanced Research Training Course for useful discussions and comments. M.V. is supported by the Human Frontier Science Program (HFSP) fellowship LT000283-2020-C. E.D.S. is supported by National Science Foundation (NSF) grant No. 2013131.

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Correspondence to Ali H. Brivanlou.

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A.H.B. and E.D.S. are co-founders of RUMi Scientific. A.H.B. is the co-founder of OvaNova Laboratories. M.V. declares no competing interests.

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Glossary

Rheology

The structural properties of a material that predict its dynamical behaviour when subject to a defined stress.

Bottle cells

In the early Xenopus laevis gastrula, elongated epithelial cells undergoing apical constriction at the site of the blastopore formation.

Blastopore

A circular and transient morphological structure located on the dorsal side in amphibians, through which the mesoderm is internalized during early gastrulation.

Convergent extension

Tissue-scale deformation, whereby the tissue stretches in one direction and narrows in the orthogonal axis owing to the radial intercalation of cells into the elongating layer.

Blastomeres

Cells produced by the early cleavages of the zygotic egg.

Force fields

Continuous force descriptions that represent as a vector field the physical interactions in a given system. For instance, in a developing embryo, a coarse-grained representation in which each individual force to which a cell is submitted within a tissue is computed.

Trophectoderm

An extra-embryonic tissue forming the outer layer of the mammalian blastocyst that envelops the embryo proper and supplies nutrients.

Durotaxis

A mode of cellular migration in which cells follow stiffness gradients as a long-range cue.

Jamming–unjamming

A special type of phase transition where increasing (jamming) or decreasing (unjamming) the packing of particles in a granular material leads to a macroscopic viscosity change. This theoretical framework has been used to describe the packing of cells in a biological tissue.

Wetting

The spreading of a liquid phase on top of another phase owing to favoured heterotypic interactions between the constituents of the two phases.

Epithelial–mesenchymal transition

A cellular transition whereby polarized epithelial cells lose adhesion with respect to one another and become independent (mesenchymal) and mobile. There is a spectrum of epithelial–mesenchymal transitions: that is, not all epithelial–mesenchymal transitions lead to fully mesenchymal cells.

Morphogen

As defined historically by Turing, a molecule secreted by a group of cells and acting from a distance on another group of cells, eliciting different outcomes in a dose-dependent manner.

Mechanical instabilities

Instabilities that appear when small fluctuations around an unstable equilibrium position drive the system towards two very different outcomes. The wrinkling or buckling of epithelial sheets is an example of a mechanical instability.

Mechano-transduction

Processes that convert extrinsic mechanical signals (for example, environmental stiffness or a force from a neighbouring cell) into an intrinsic change in the intracellular biochemical, transcriptional or bioelectrical activity of the cell.

Planar cell polarity (PCP) pathway

The signalling pathway that regulates the polarization of a field of cells within the plane of a cell sheet. This process is involved in various developmental events, including convergent extension.

Hippo pathway

The signalling pathway associated with cell proliferation, tissue and organ growth, size determination and mechanosensation.

Nodal

A morphogen belonging to the super TGFβ family, initially named because of its association with the node structure in the developing mouse embryo.

Node

A small structure at the anterior part of the primitive streak.

Basal body

A protein structure found at the basis of eukaryotic cilia that serves as a nucleation site for microtubules.

Chiral molecules

Molecules that cannot be superposed to their mirrored image by any combination of rotations. Chiral molecules often have different reactivities.

Primitive streak

A transient embryonic tissue acting as a signalling centre and a point of conversion to mesendoderm. Morphologically, an elongated depression that progresses from the posterior to the anterior part of the epiblastic disc.

Involution

Specific morphogenetic event happening during gastrulation that involves the collective motion of cells that spread inwards by rolling around a boundary imposed by bottle cells, leading to basal to basal juxtaposition of the internal and external cells.

Convergent thickening

A process whereby cells rearrange themselves and leave the surface of the tissue to invade the space in-between, leading to shortening and thickening of the tissue.

Epiboly

The partial enveloping of one cell population by another in early developmental processes, owing to proliferation differences between the two tissues.

Neural crest

A transient cell population in vertebrates that originates from the ectoderm.

Surface tension

Modelized as a force per unit of length or as an energy per unit of area, tension that results from the cost of maintaining an interface between two fluid-like systems having a homotypic interaction (between molecules or cells of the same type) more favourable than the heterotypic interaction (between molecules or cells of a different type).

Ephrin signalling pathway

A cell–cell signalling mechanism involving, on one side, Eph receptor kinases (transmembrane proteins) and, on the other, their membrane-tethered ligands called ephrins. This signalling has been intensely investigated in the context of the nervous system development and is involved in cell sorting, positioning and migration.

Blastoderm

Usually, the initial population of embryonic superficial cells on top of the yolk (in a yolky embryo such as the chick or the zebrafish).

Competence

For an embryonic cell, being competent means being able to respond to inductive signals. As mechanics shape the potential of cells to be responsive in a specific time and space window, it is likely that competence is also affected by mechanical forces.

Gastruloids

In vitro assembled 2D or 3D aggregates of pluripotent embryonic cells that model some aspects of in vivo gastrulation, whereby cells self-organize to generate patterns of embryonic and extra-embryonic tissues.

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Valet, M., Siggia, E.D. & Brivanlou, A.H. Mechanical regulation of early vertebrate embryogenesis. Nat Rev Mol Cell Biol 23, 169–184 (2022). https://doi.org/10.1038/s41580-021-00424-z

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