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Cytoskeletal control of early mammalian development

Abstract

The cytoskeleton — comprising actin filaments, microtubules and intermediate filaments — serves instructive roles in regulating cell function and behaviour during development. However, a key challenge in cell and developmental biology is to dissect how these different structures function and interact in vivo to build complex tissues, with the ultimate aim to understand these processes in a mammalian organism. The preimplantation mouse embryo has emerged as a primary model system for tackling this challenge. Not only does the mouse embryo share many morphological similarities with the human embryo during its initial stages of life, it also permits the combination of genetic manipulations with live-imaging approaches to study cytoskeletal dynamics directly within an intact embryonic system. These advantages have led to the discovery of novel cytoskeletal structures and mechanisms controlling lineage specification, cell–cell communication and the establishment of the first forms of tissue architecture during development. Here we highlight the diverse organization and functions of each of the three cytoskeletal filaments during the key events that shape the early mammalian embryo, and discuss how they work together to perform key developmental tasks, including cell fate specification and morphogenesis of the blastocyst. Collectively, these findings are unveiling a new picture of how cells in the early embryo dynamically remodel their cytoskeleton with unique spatial and temporal precision to drive developmental processes in the rapidly changing in vivo environment.

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Fig. 1: Key structures formed by the cytoskeleton during embryo compaction and polarization.
Fig. 2: Cytoskeletal heterogeneities between cells that promote inner cell versus outer cell segregation.
Fig. 3: Dynamic cytoskeletal reorganization during asymmetric cell divisions.
Fig. 4: Cytoskeletal elements regulating the acquisition of lineage fates in the early embryo.
Fig. 5: Cytoskeletal changes driving blastocyst formation.

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Acknowledgements

This work was supported by an A*STAR Graduate Scholarship to H.Y.G.L. and US National Institutes of Health grant R01GM1399700-1 and HD102013-01A1 to N.P.

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Correspondence to Nicolas Plachta.

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Glossary

Linker of nucleoskeleton and cytoskeleton

(LINC). Protein complex spanning the inner and outer nuclear membrane, connecting chromatin from within the nucleus to cytoskeletal filaments and organelles within the cytoplasm.

Trophectoderm

A layer of differentiated cells located on the outer surface of the blastocyst, which eventually form the embryonic part of the placenta. These are the first epithelial-like cells that form during development.

Inner cell mass

(ICM). Pluripotent cells located within the inner part of the blastocyst, which subsequently form the developing fetus and other supporting extraembryonic tissues.

Primitive endoderm

One of two lineages derived from the inner cell mass, along with the epiblast, which generates the extraembryonic yolk sac that supports the growth of the fetus.

PAR–aPKC complex

The PDZ domain-containing scaffold proteins PAR3 and PAR6 together with the serine/threonine kinase atypical protein kinase C (aPKC), which are key regulators of epithelial cell polarity.

Apical domain

In the context of the mouse embryo, a polarized group of proteins organized in the form of a rounded patch at the contact-free exposed apical surface of 8-cell-stage blastomeres.

Acetylated microtubules

A post-translational modification on tubulin that stabilizes microtubule filaments.

Keratin

A class of intermediate filament proteins expressed in epithelial cells best known for its mechanical strength.

Micropipette aspiration

Method of measuring cortical tension in a living cell system. A known suction force is applied through a micropipette to aspirate the cell surface, and the resulting cell deformation within the micropipette is measured.

Filopodia

Actin-based cellular protrusions typically used for sensing of the cell’s external environment.

Myosin X

An unconventional plus-end myosin motor localized within actin-based protrusions, including lamellipodia and filopodia.

Laser ablation

Method of specifically ablating or cutting subcellular structures within a living system using a high-energy laser beam.

Morphogens

Molecules whose specific spatial distribution pattern within a developing tissue or organism regulates fate specification and morphogenesis.

RHOA

Ras homologue family member A, a Rho-family GTPase with key roles in promoting actin polymerization and actomyosin contractility.

TFAP2C

Transcription factor AP-2γ, a DNA-binding protein regulating the transcription of many genes, including the trophectoderm lineage marker Cdx2.

TEAD4

TEA domain transcription factor 4, a transcription factor involved in activating the trophectoderm lineage transcriptional programme, including Cdx2 expression.

ARP2/3 complex

A protein complex containing actin-related protein 2 (ARP2) and ARP3 subunits that functions as a major nucleator of actin filaments, generating branched actin networks.

Apical constriction

Myosin II-dependent coordinated narrowing of the apical part of cells located within an epithelial cell sheet, often resulting in tissue-level changes in epithelium morphology.

Hertwig’s long-axis rule

A prediction of division orientation occurring along the longest cell axis.

Centrosomes

Primary microtubule-organizing centre in many animal cells, made up of two centrioles and a dense mass of pericentriolar material.

Microtubule-organizing centres

(MTOCs). Sites of microtubule polymerization within the cell.

Astral microtubule arrays

Microtubules emanating from the centrosome towards the cell surface that aid in spindle positioning during mitosis.

Meiosis I

The first of two rounds of cell division ultimately giving rise to mature gametes.

Polar body

A small cell produced during the asymmetric meiotic divisions that generate the larger, mature oocyte.

Formin 2

An actin nucleator promoting the polymerization of existing actin filaments.

Neuroblasts

Neural stem cells in the Drosophila melanogaster embryo.

Ventral furrow

The large-scale invagination of cells located on the ventral surface of the Drosophila melanogaster embryo that produces the embryonic mesoderm.

Adherens junction

A class of junctional complexes mediating cell–cell adhesion via cadherin interactions, with links to the actin cytoskeleton via adaptor proteins, including α-catenin and β-catenin.

Hippo signalling pathway

A major signalling pathway involved in the regulation of organ size during development and homeostasis.

Desmosome

Also known as macula adherens, a hyperadhesive intercellular adhesion complex composed of extracellular cadherin family proteins and intracellular scaffold and linker proteins connecting the complex to the intermediate filament cytoskeleton.

Plakin family

A family of proteins, including desmoplakin, plectin and periplakin, which function as crosslinkers between cytoskeletal filaments and connect the cytoskeleton to junctional complexes.

Mechanosensor

A cellular structure/component able to detect and respond to changes in mechanical stimuli, such as by altering its molecular conformation and binding partners.

Actin ring

F-actin filaments organized in the form of a ring on the apical cortex of outer blastomeres in the 16-cell-stage embryo. These rings display low levels of myosin II and expand to cell–cell junctions, where they zipper and establish mature tight and adherens junctions.

Tight junction

An adhesion complex typically located at the apical-most portion of cell–cell junctions that facilitates the establishment of a sealed barrier.

ZO1

Zonula occludens protein 1, a scaffolding protein within tight junction complexes that connects them to the actin cytoskeleton.

Occludin

Transmembrane protein component of tight junctions, functioning together with ZO1 and the claudin family of proteins.

Aquaporins

Channel proteins spanning the cell membrane, through which water can be transported in and out of the cell.

Light-sheet microscopy

An imaging system using a thin sheet of illumination light that is oriented perpendicular to the detector, which greatly reduces the out-of-focus excitation and photobleaching from which traditional confocal methods suffer.

Super-resolution microscopy

An imaging system providing spatial resolution higher than the diffraction limit of traditional microscopes. Common super-resolution techniques include stimulated emission depletion microscopy, photoactivated localization microscopy and stochastic optical reconstruction microscopy.

Particle-tracking microrheology

A method of tracking the movement of inert, fluorescent beads within the cytoplasm of living cells to measure their viscoelastic properties.

Optogenetic-driven techniques

The use of light to precisely control the subcellular localization or functions of light-sensitive proteins.

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Lim, H.Y.G., Plachta, N. Cytoskeletal control of early mammalian development. Nat Rev Mol Cell Biol (2021). https://doi.org/10.1038/s41580-021-00363-9

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