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Calcium

Calcium signalling during embryonic development

Key Points

  • Many features of Ca2+ signalling that have been described previously in mature cells and tissues are now being found to occur and be associated with events during embryogenesis.

  • The elementary Ca2+ events that constitute intracellular signalling during fertilization and early zygotic developmental stages are thought to form the basis of many, if not all, of the subsequent intracellular and intercellular signalling events that occur as development proceeds.

  • As development progresses, the increase in embryonic cell number is accompanied by a reduction in cell size, with the result that individual cells become surrounded by an increasing number of neighbouring cells. This increase in complexity is accompanied by developmental events being initiated that require coordinated activity and, as a consequence, there is an initiation of localized intercellular Ca2+ signalling.

  • During the extensive cellular rearrangements that occur during gastrulation, germ-layer formation and establishment of the body axes, there is an increased requirement for coordination on a broader scale. This is reflected in the intercellular Ca2+-signalling events that, likewise, begin to display a more extensive global nature.

  • Once the germ layers and major body axes have been established, there is a return to more localized intercellular signalling events that are associated with the generation of specific embryonic organs such as the brain and heart, and a reappearance of intracellular signalling events from single cells.

  • Efforts to identify the downstream targets and overall function of these Ca2+ signals in specific developmental events are now in progress.

Abstract

Consider a hypothetical design specification for an integrated communication-control system within an embryo. It would require short-range (subcellular) and long-range (pan-embryonic) abilities, it would have to be flexible and, at the same time, robust enough to operate in a dynamically changing environment without information being lost or misinterpreted. Although many signalling elements appear, disappear and sometimes reappear during development, it is becoming clear that embryos also depend on a ubiquitous, persistent and highly versatile signalling system that is based around a single messenger, Ca2+.

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Figure 1: Ca2+ signalling during six stages of zebrafish development.
Figure 2: Localized Ca2+ signalling during the blastula period of zebrafish development.
Figure 3: A pan-embryonic intercellular Ca2+ wave at 75% epiboly (8 hpf) in zebrafish.
Figure 4: Resumption of more localized intercellular Ca2+ signalling during segmentation.
Figure 5: Localized intercellular Ca2+ signals generated by developing somites of a 18-hpf zebrafish.
Figure 6: Possible mechanisms for generating intercellular Ca2+ signals.

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Acknowledgements

Work on this topic in the authors' laboratory is supported by the Research Grants Council of Hong Kong and the National Natural Science Foundation of China. We also thank O. Shimomura for his generous contribution to aequorin-based imaging over the years.

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Correspondence to Andrew L. Miller.

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DATABASES

Entrez

N-cadherin

LocusLink

calreticulin

CamKII

dpp

Ins(1,4,5)P3Rs

PKD1

PKD2

RYRs

Swiss-Prot

annexin IV

BMP7

β-catenin

cdc42

Frizzled-2

Wnt-1

Wnt-5A

XNF-AT

FURTHER INFORMATION

HKUST calcium-aequorin imaging laboratory

Glossary

BLIP

A Ca2+ signal that is the result of the opening of an individual inositol-1,4,5-trisphosphate receptor.

QUARK

A Ca2+ signal that is the result of the opening of an individual ryanodine receptor.

PUFF

A Ca2+ signal that is the result of the opening of groups of inositol-1,4,5-trisphosphate receptors.

SPARK

A Ca2+ signal that is the result of the opening of groups of ryanodine receptors.

INTRACELLULAR CA2+ WAVE

A Ca2+ signal that is the result of neighbouring receptors exciting each other to produce a wave of Ca2+-induced Ca2+ release.

BLASTULA

In many animals, this is a hollow ball of cells that forms between the cleavage and gastrula stages. Although such a structure doesn't form in zebrafish, this term is still used to refer to the same stage of development.

ENVELOPING LAYER

(EVL). The cells that make up the most superficial layer (that is, the periderm) of the blastoderm in zebrafish.

PERIDERM

A superficial monolayer that is only present early in development and protects the underlying epidermis until it is fully formed.

INOSITOL-1,4,5-TRISPHOSPHATE RECEPTOR

 (Ins(1,4,5)P3R). A Ca2+-release channel that is located in the membrane of the endoplasmic reticulum and is regulated by several factors, including Ca2+ itself and the second messenger Ins(1,4,5)P3.

ANIMAL AND VEGETAL POLES

In embryos that contain significant quantities of yolk, the animal pole is the region that contains the nucleus (or nuclei) and most of the cytoplasm, whereas the vegetal pole lies opposite the animal pole and contains most of the yolk. It has been suggested for many species that there are gradients of important growth factors along the animal pole–vegetal pole axis that have a key role in embryonic patterning.

GASTRULA

An early stage in the development of many animal embryos that follows the blastula stage. It usually consists of a double-layered ball of cells formed by a series of complex cell movements that transforms the single-layered blastula into a gastrula.

SHIELD

The embryonic shield in zebrafish is an organizer domain that is functionally equivalent to the dorsal blastopore lip in amphibian embryos or Hensen's node in the chick.

NEURAL KEEL

A transient structure that is formed during the morphogenesis of the central nervous system primordium in zebrafish. It appears between the formation of the neural plate and the neural rod along the dorsal midline of the embryo, and is roughly triangular in cross section, which explains its name.

SYNCYTIAL BLASTODERM

A rapid series of nuclear divisions without cytoplasmic divisions that results in a syncytial or multinuclear single-cell Drosophila embryo.

MORPHOGEN

A general term for any substance that influences morphogenesis or embryonic development.

EPIBOLY

The movement of sheets of cells that spread as a unit, rather than individually, to enclose the deeper layers of an embryo. In zebrafish, this term describes the thinning and spreading of the blastoderm over and across the yolk cell, eventually encompassing the yolk cell completely.

INVOLUTION

The turning inwards, or inward movement, of an expanding outer layer of cells, so that it spreads over the internal surface of the remaining external cells. This process converts a single-layered blastula into a double-layered gastrula.

CONVERGENCE

The movement of cells towards the dorsal midline. This occurs simultaneously with extension and is therefore also referred to as convergent extension.

EXTENSION

The movement of cells towards the anterior end of the dorsal midline. This occurs simultaneously with convergence and is therefore also referred to as convergent extension.

CHORION

An extra-embryonic membrane that surrounds the zebrafish embryo during the first two days of development.

KELLER OPEN-FACE EXPLANT

Tissue containing both ectoderm and mesoderm, extending from the blastopore lip up to the animal pole, is excised from Xenopus embryos at stage 10 (9 hours postfertilization). The explant is then cultured flat under a cover slip, so that involution of the mesoderm cannot take place. This two-dimensional model system has been used to study both neural induction and convergence and extension movements in Xenopus embryos.

L-TYPE VOLTAGE-SENSITIVE CA2+ CHANNELS

A class of voltage-dependent Ca2+ channels (also known as dihydropyridine- or DHP-sensitive channels) that are located in the plasma membrane, require a membrane potential greater than −30 mV for activation and are commonly found in neurons, neuroendocine cells and muscle cells.

NEURAL TUBE

A hollow tube of ectodermal tissue, which forms down the central axis of early vertebrate embryos, and from which the brain and spinal cord will develop.

NEURAL PLATE

The thickened plate of ectoderm from which the neural tube develops.

RYANODINE RECEPTOR

(RYR). A Ca2+-release channel that is located in the membrane of the sarcoplasmic and endoplasmic reticulum, and that is regulated by protein–protein interactions with the dihydropyridine receptor and by several factors, including Ca2+ itself.

GROWTH CONE

The highly motile leading edge of extending axons and dendrites in developing neurons.

AEQUORIN

A Ca2+-sensitive bioluminescent reporter that was originally isolated from the jellyfish Aequoria victoria. It is made up of the 20-kDa apoaequorin protein, the 420-Da luminophore coelenterazine and molecular oxygen. When two Ca2+ ions bind to the complex, the coelenterazine is oxidized to coelenteramide, and CO2 and blue light (465 nm) are produced.

PRONEPHROS

This is the first kidney to develop, later being replaced by the mesonephros and the metanephros. It is the most simple of the three types of kidney and is the functional embryonic kidney in lower vertebrates.

F-ACTIN

(filamentous actin). This forms the microfilaments of the cytoskeleton and the thin filaments of muscle. It is made of two chains of actin monomers that are wound around one another in a helix.

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Webb, S., Miller, A. Calcium signalling during embryonic development. Nat Rev Mol Cell Biol 4, 539–551 (2003). https://doi.org/10.1038/nrm1149

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