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Developmental cell biology

Making digit patterns in the vertebrate limb

Nature Reviews Molecular Cell Biology volume 7, pages 45–53 (2006)Cite this article

Key Points

  • Experiments on the limb buds of chick embryos led to the identification of the polarizing region and the characterization of signalling properties that lead to the morphogen-gradient model.

  • The specification of positional values involves several signalling molecules, such as sonic hedgehog (SHH) and GLI.

  • SHH has been identified as the polarizing-region morphogen, whereas the downstream signalling molecule bone morphogenic protein-2 (BMP2) might only be able to specify positional values in cells already 'primed' by SHH.

  • Sophisticated fate maps in mouse embryos revealed that the length of time that cells are exposed to the highest concentrations of SHH might contribute to digit patterning. This led to a detailed model for specification of positional values for each mouse digit, which integrates both concentration and length of exposure to SHH.

  • Probable candidates for genes that could encode antero–posterior positional values are the homeobox (Hox) genes and orthologues of fruitfly wing-patterning genes.

  • Evidence from studies on chick legs indicates that the morphogenesis of each individual digit involves local interactions. Signalling molecules in digit primordia, such as BMPs and fibroblast growth factors (FGFs), give rise to the final digit morphology.

Abstract

The vertebrate limb has been a premier model for studying pattern formation — a striking digit pattern is formed in human hands, with a thumb forming at one edge and a little finger at the other. Classic embryological studies in different model organisms combined with new sophisticated techniques that integrate gene-expression patterns and cell behaviour have begun to shed light on the mechanisms that control digit patterning, and stimulate re-evaluation of the current models.

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Figure 1: The three main axes of the human hand.
Figure 2: Models for specifying antero–posterior positional values in the chick wing and the mouse limb.
Figure 3: Cell–cell signalling in the digital plate.

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Acknowledgements

I would like to thank M. Fisher and M. Towers for useful discussions, as well as M. Fisher for producing Fig. 2 and A. Bain for producing Fig. 1. I would also like to acknowledge A. Blake for her help with preparing the manuscript and the Medical Research Council and The Royal Society for supporting my research.

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Authors and Affiliations

  1. Division of Cell and Developmental Biology, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, UK

    Cheryll Tickle

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  1. Cheryll Tickle
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DATABASES

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Hh

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Omb

Spalt

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GLI1

GLI2

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FURTHER INFORMATION

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Glossary

Mesenchyme

A loose meshwork of cells found in vertebrate embryos, which is usually derived from the mesoderm, the middle of the three germ layers.

Ectoderm

The epithelium that is derived from the outer of the three germ layers of the embryo and will give rise to the epidermis of the skin.

Positional information

The instructions that are interpreted by cells to determine their differentiation with respect to their position within the embryo.

Morphogen

A diffusible chemical substance that carries information in embryos, for example, cell position.

Tbx family

Related transcription factors that contain a T-Box.

Apical ectodermal ridge

Thickening of the ectoderm rim at the tip of a developing limb bud in a vertebrate embryo. It is required for bud outgrowth.

Polarizing activity

The ability of cells, tissue or defined chemicals to induce the formation of extra digits from the anterior region of a chick limb bud.

Fate map

A diagram that is obtained experimentally by tracing marked cells and shows the structures that derive from cells in different regions of an embryo.

Digital plate

Broad region that forms late during limb development at the distal end of the bud and contains the digit primordia.

Humerus

The single bone in the upper arm, initially laid down in cartilage.

Polydactylous

Having more than the normal number of digits.

Intraflagellar transport proteins

Proteins that associate with, or in, a flagellum or cilium and the associated basal body.

Reaction–diffusion mechanism

Self-organizing system that consists of two or more interacting chemical substances and spontaneously generates spatial patterns.

Gap-junctional communication

Mechanism of direct cell–cell communication in which small molecules pass through aligned gap junctions on neighbouring cells and not extracellularly.

β-galactosidase

β-Galactosidase is a commonly used reporter molecule, which can be readily visualized.

Paralogous

A sequence, or gene, that originates from a common ancestral sequence, or gene, by a duplication event. For example, as seen in Hoxd gene clusters and designated by a number from 1–13.

Mammary-ulnar syndrome

Rare human congenital condition that is characterized by specific defects in both mammary glands and limbs.

Haploinsufficiency

Defines a genetic condition in which the defect is seen in heterozygous individuals.

Phalanx

(plural phalanges). One of the series of small bones that make up the fingers and toes in vertebrates.

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Tickle, C. Making digit patterns in the vertebrate limb. Nat Rev Mol Cell Biol 7, 45–53 (2006). https://doi.org/10.1038/nrm1830

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