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  • Review Article
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Developmental cell biology

G proteins in development

Nature Reviews Molecular Cell Biology volume 6, pages 689–701 (2005)Cite this article

Key Points

  • Development is a progressive, dynamic process that involves coordination between cell signalling and gene expression. Heterotrimeric G proteins are well-known mediators of various cell signalling pathways, but their roles in development have been poorly understood.

  • G proteins have been identified in some plants and in all animals from Drosophila melanogaster to humans, including roundworms, the sea urchin, zebrafish, frogs and rodents. G proteins have been implicated as essential transducers in all main models of development.

  • Many heptahelical cell-membrane-localized receptors have been implicated in development, including the Frizzled proteins, the methuselah gene product and perhaps Smoothened. Use of knockout mice and knock-down technologies in cells enables the elucidation of the precise identity of the G proteins that transduce the binding of agonists (for example, Wnts) to the receptor (Frizzled) into effector activation.

  • The superfamily of G-protein-coupled receptors (GPCRs) functions through a smaller family of G proteins that can signal both by their activated, GTP-bound Gα subunits as well as their Gβγ-subunit complexes, which activates G-protein-coupled effectors. Effectors of G proteins include the well-known adenylyl cyclases, phosphodiesterases, phospholipase Cβs and various ion channels.

  • GPCRs can activate several G proteins, which in turn can activate several effectors that are linked to downstream signalling cascades, such as the mitogen-activated-protein-kinase cascades. These cascades link G-protein activation to changes in gene transcription and expression and to rearrangement of the cytoskeleton.

  • G-protein-based signalling complexes make use of scaffold molecules, such as the A-kinase anchoring proteins (AKAPs), which provide a mobile toolbox of protein kinases, protein phosphatases and adaptor molecules to modulate signals from the GPCRs to the signalling cascades. Scaffolds confer spatial localization on signalling complexes in cells, an important facet of early development in which axis and morphogen gradients function.

  • G proteins are regulated not only by activated GPCRs, but also by members of several classes of newly discovered modulators, including regulators of G-protein signalling (RGS proteins), activators of G-protein signalling (AGS proteins), and partners of Inscuteable (Pins). G proteins have essential roles in the formation and orientation of mitotic spindles, in planar cell polarity, and in Frizzled signalling.

Abstract

The focus of developmental biologists has expanded from the analysis of gene expression to include the analysis of cell signalling. Heterotrimeric G proteins (G proteins) mediate signalling from a superfamily of heptahelical receptors (G-protein-coupled receptors) to a smaller number of effector units that include adenylyl cyclases, phospholipase C and various ion channels. The convergence of developmental biology with cell signalling has now revealed overlaps in which G proteins mediate complex pathways in embryonic development.

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Figure 1: G-protein-mediated signalling pathways.
Figure 2: Role of scaffold molecules in G-protein-signalling-complex formation and spatial localization.
Figure 3: Trafficking of G-protein signalling complexes: the spatial dimension.
Figure 4: The functions of G proteins in development.

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Acknowledgements

I thank the members of the Malbon laboratory, and especially Dr. H.-Y. Wang, Department of Physiology and Biophysics, State University of New York at Stony Brook, for the critical reading of the manuscript, M. Feigin for assistance in compiling the tables, E. Shumay for the fluorescence images, and R. Brockner for help with the references and with the compilation of background material. This work was generously supported by a National Institutes of Health grant to C.C.M.

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Authors and Affiliations

  1. Department of Pharmacology, School of Medicine, Health Sciences Center, State University of New York at Stony Brook, Stony Brook, 11794-8651, New York, USA

    Craig C. Malbon

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  1. Craig C. Malbon
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DATABASES

Flybase

aPKC

Baz

Frizzled

Inscuteable

loco

methuselah

Par6

Pins

Smoothened

OMIM

Albrights hereditary osteodystrophy

McCune–Albright syndrome

Swiss-Prot

AKAP250

LARG

p115-RhoGEF

PDZ-RhoGEF

Wormbase

EAT-16

EGL-10

GPB-1

GPR-1

GPR-2

SRA-13

FURTHER INFORMATION

Craig Malbon's laboratory

Glossary

G-PROTEIN EFFECTOR

A protein that is directly downstream of G proteins in the signalling pathway. This protein responds to the activation of either a heterotrimeric G-protein α subunit or the Gβγ-subunit complex with a specific change in its activity. G-protein effectors include adenylyl cyclase, phospholipase C and various ion channels.

FATTY ACYLATION

Addition of a fatty acid moiety to N-terminal glycine by N-myristoylation and/or palmitoylation of an internal cysteine residue of a protein.

ISOPRENYLATION

Enzyme-mediated post-translational covalent attachment of a hydrophobic isoprenyl moiety to proteins.

INNER LEAFLET

A lipid layer that faces the inside of the cell.

G-PROTEIN-COUPLED RECEPTOR

(GPCR). A seven-helix membrane-spanning cell-surface receptor that signals through heterotrimeric GTP-binding and -hydrolysing G proteins to stimulate or inhibit the activity of a downstream enzyme.

GROWTH CONE

Motile tip of the axon or dendrite of a growing nerve cell that spreads out into a large cone-shaped appendage.

GASTRULATION

Series of morphogenetic movements observed during the early development of most animals that leads to the formation of a multilayered embryo with an outer cell layer (ectoderm), an inner cell layer (endoderm), and an intermediate cell layer (mesoderm).

KNOCK-DOWN

Suppression of the expression of a gene product, typically achieved by the use of antisense oligodeoxynucleotides, antisense morpholinos and RNAi that specifically target the RNA product of the gene.

PERTUSSIS TOXIN

A protein toxin composed of A and B protomers that is produced by Bordetella pertussis. It inactivates Gαi proteins by specifically catalysing ADP ribosylation of the α subunit.

TERATOCARCINOMA CELLS

Embryonal carcinoma cells derived from a malignant germ-cell tumour arising from the ovary or testis.

KNOCKOUT

A mouse product of genetic manipulation that yields the inactivation of a specific gene (that is, complete deficiency of the gene product) by gene interruption.

SYNAPTIC BOUTON

An enlargement of the presynaptic nerve terminal that contains the vesicles and apparatus for the release of the neurotransmitter.

PRIMITIVE ENDODERM

The extraembryonic tissue that gives rise to the visceral and parietal endoderm.

ASYMMETRIC CELL DIVISION

Cell division in which the derivative daughter cells are different from each other because cytoplasmic determinants have been distributed unequally.

WNT PROTEINS

A family of highly conserved secreted signalling molecules that regulate cell–cell interactions during embryogenesis.

RETINOIC ACID

A morphogen and regulator of differentiation during embryogenesis. It is a product of vitamin A, which the body synthesizes from carotenes.

PLANAR CELL POLARITY

The pattern of organization of cells in the plane of an epithelium.

MITOTIC SPINDLE

A bipolar array of microtubules that forms during mitosis, to which chromosomes attach and by which chromosomes are segregated to daughter cells.

HANDEDNESS

Asymmetry of internal organs (such as the heart, lung and liver) with respect to left and right sides in organisms with bilateral body symmetry for structures such as eyes, ears and limbs.

HYDROPATHY PLOT

A measure of the hydrophobicity of a protein region that provides an indication of the likelihood that it will reside in a membrane.

CYCLIC-NUCLEOTIDE-GATED CHANNEL

(CNGC). Conserved protein family with six predicted transmembrane helices that can form cation-conducting channels and that is activated by the binding of cyclic nucleotides such as cAMP and cGMP.

CELL DIFFERENTIATION

A normal process in development in which cells become structurally and functionally different from one another and develop a mature phenotype — for example, fat, muscle and liver cells.

GUANINE NUCLEOTIDE-EXCHANGE FACTOR

A protein that activates a specific small GTPase by catalysing the exchange of bound GDP for GTP.

MORPHOGEN

A substance that induces pattern formation, differentiation and morphogenesis. The concentration of a morphogen often forms a gradient to which cells respond differently.

GTPase-ACTIVATING PROTEIN

(GAP). Proteins that inactivate small GTP-binding proteins, such as Ras-family members, by increasing their rate of GTP hydrolysis.

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Malbon, C. G proteins in development. Nat Rev Mol Cell Biol 6, 689–701 (2005). https://doi.org/10.1038/nrm1716

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