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Vertebrate limb bud development: moving towards integrative analysis of organogenesis

Key Points

  • Analyses of vertebrate limb bud development continue to provide fundamental insights into how vertebrate organogenesis is orchestrated.

  • Classical patterning signals coordinate specification and determination with proliferation and survival. The underlying interactions define self-regulatory and robust signalling systems that interlink multiple pathways.

  • A first integrative, data-driven model of limb organogenesis is presented, which should stimulate holistic and systems biology approaches for studying limb development and organogenesis more broadly.

Abstract

The limb bud is of paradigmatic value to understanding vertebrate organogenesis. Recent genetic analysis in mice has revealed the existence of a largely self-regulatory limb bud signalling system that involves many of the pathways that are known to regulate morphogenesis. These findings contrast with the prevailing view that the main limb bud axes develop largely independently of one another. In this Review, we discuss models of limb development and attempt to integrate the current knowledge of the signalling interactions that govern limb skeletal development into a systems model. The resulting integrative model provides insights into how the specification and proliferative expansion of the anteroposterior and proximodistal limb bud axes are coordinately controlled in time and space.

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Figure 1: Proximodistal limb bud axis development.
Figure 2: Anteroposterior limb bud axis development.
Figure 3: Interlinked feedback loops define a self-regulatory limb signalling system.
Figure 4: An integrative model for limb bud development.

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Acknowledgements

We are indebted to C. Müller-Thompson, J. D. Benazet, A. Galli, C. Vaillant and the three reviewers for their critical input and discussions. We wish to apologize to all our colleagues whose important contributions could not be discussed and/or referenced owing to space limitations. Our research on limb development is supported by the Swiss National Science Foundation, the European Union Marie Curie Fellowship program and the University of Basel.

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Correspondence to Rolf Zeller.

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DATABASES

OMIM

acheiropodia

preaxial polydactylies

FURTHER INFORMATION

Developmental Genetics research group, University of Basel

Glossary

Specification

The process preceding determination during which a cell acquires its fate. The exposure of specified cells to different signals might alter their fates; the fate of specified cells is not fixed (unlike determined cells).

Determination

When cell fate is fixed so that the cell will initiate differentiation into the specified cell type even if the cell is isolated or transplanted into a different environment or tissue. Determination occurs before the appearance of cell-type-specific morphological characteristics, but is often closely followed by the initiation of differentiation.

Patterning

The process in which the positions and identities of cells with different fates are laid down.

Apical ectodermal ridge

A specialized epithelium that is required for limb bud outgrowth. It runs along the distal tip of the limb bud and expresses several fibroblast growth factors. During the initiation of limb bud development, the ridge forms at the dorsoventral interface of the limb bud ectoderm.

Epithelial–mesenchymal feedback loop

Signalling interactions between an epithelium and the adjacent mesenchyme. These interactions of different signals from both compartments form a closed feedback loop. The development of many organs is controlled by epithelialmesenchymal feedback loops.

Fate mapping

Following the fates and progeny of cells during embryonic development by marking them with lipophilic dyes or recombinant retroviruses, or by using molecular genetic tools that result in permanent expression of an inert marker gene, such as β-galactosidase or GFP.

Fate

The fate of a cell is normally dependent on specific inductive signals. After their fate is determined, cells will normally follow a specific developmental sequence towards differentiation into a particular cell type.

Differentiation

When cells activate genes that result in the appearance of cell-type-specific characters. During embryonic development, groups of cells that have been determined will initiate differentiation into specific functional tissues.

Organizer

A small group of embryonic cells that have the ability to influence the fate, survival and/or proliferative potential of other cells. Grafting organizer cells to ectopic positions will induce ectopic structures (for example, mirror-image duplications of digits). Organizer cells secrete signals or antagonists that can act as morphogens.

Polydactyly

From the Greek for 'many fingers'. Limb skeletal phenotypes that result in the formation of additional digits. There are three types of polydactylies: postaxial (affecting the little finger), preaxial (affecting the thumb) and central (affecting the ring, middle and index fingers).

Cylopamine

A small molecule that inhibits all hedgehog signal transduction by binding to the smoothened seven-transmembrane receptor.

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Zeller, R., López-Ríos, J. & Zuniga, A. Vertebrate limb bud development: moving towards integrative analysis of organogenesis. Nat Rev Genet 10, 845–858 (2009). https://doi.org/10.1038/nrg2681

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