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Pattern formation: old models out on a limb

Nature Reviews Genetics volume 4, pages 133–143 (2003)Cite this article

Key Points

  • Recent results from experiments in chick and mouse have challenged previous ideas of how the vertebrate limb develops.

  • Fibroblast growth factors (FGFs) are crucial signals from the apical ectodermal ridge (AER) that direct proximal–distal (Pr–D) growth of the limb.

  • FGF signalling establishes the initial limb-bud size, regulates cell viability and proliferation, and controls mesenchyme cell number to enable skeletal condensations of correct size to form.

  • Fate-mapping studies indicate that Pr–D fates are segregated and stratified in the early limb bud.

  • These studies provide new mechanisms for thinking about how the AER enables the realization of Pr–D pattern. This differs from the progress zone model, which indicates that the AER acts to maintain a 'progress zone', where Pr–D fates are progressively specified over time.

  • Genetic studies indicate that the Sonic hedgehog (Shh) signalling molecule acts through the Gli3 transcription factor to regulate the morphology of the autopod (hand/foot) by controlling the number of digits formed and their pattern.

Abstract

The vertebrate limb is an excellent model for studying fundamental aspects of embryonic development. Cell proliferation, death and movement, and the assignment and interpretation of positional information, must be coordinated if an exquisitely patterned limb is to form. Recent results from gene targeting in mice and from experimental manipulation of the chick embryonic limb have significantly altered the way in which developmental biologists have conceptualized limb patterning.

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Figure 1: Signalling pathways in vertebrate limb development.
Figure 2: Experimental phenotypes in chick and mouse limb.
Figure 3: Graphical comparison of the progress zone and Dudley et al. models.

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Authors and Affiliations

  1. Howard Hughes Medical Institute, Molecular Biology Programme, Sloan–Kettering Institute, 1275 York Avenue, Box 73, New York, 10022, New York, USA

    Lee Niswander

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  1. Lee Niswander
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DATABASES

LocusLink

Bmp2

Bmp4

Bmp7

Bmpr1a

dHand

En1

Fgf4

Fgf8

Fgf9

Fgf10

Fgf17

Gli1

Gli2

Gli3

Lmx1b

Ptc1

Wnt3a

Wnt7a

Arkdb

Shh

Glossary

MESENCHYME

Embryonic tissue that is composed of loosely organized, unpolarized cells of both mesodermal and ectodermal (for example, neural crest) origin, with a proteoglycan-rich extracellular matrix.

STYLOPOD

The proximal element of a limb that will give rise to the humerus in the forelimb and the femur in the hindlimb.

ZEUGOPOD

The intermediate elements of a limb that will give rise to the radius and ulna in the forelimb, and the tibia and fibula in the hindlimb.

AUTOPOD

The distal elements of a limb that will give rise to the wrist and the fingers in the forelimb, and the ankle and toes in the hindlimb.

CRE-LOX SYSTEM

A site-specific recombination system that is derived from the Escherichia coli bacteriophage P1. Two short DNA sequences (loxP sites) are engineered to flank the target DNA. Activation of the Cre recombinase enzyme catalyses recombination between the loxP sites, which leads to the excision of the intervening sequence.

MORPHOGEN

A diffusible signal that acts at a distance to regulate pattern formation in a dose-dependent manner.

POLYDACTYLY

Having more than the normal number of digits.

SPECIFICATION

A cell or tissue is specified to become a particular structure if, when isolated and placed in a neutral medium, it develops autonomously into that structure. Specification might still be reversed or altered following exposure to a different environment. Specification of a region need not be the same as its fate in normal development.

FATE MAP

Shows how a cell or tissue moves and what it will become during normal development, although the commitment of the cell or tissue cannot be inferred from the fate map.

DETERMINATION

Irreversible commitment of a cell or tissue. Pattern is fixed such that even if cells are exposed to different tissues or signals they will continue to develop according to their intrinsic pattern.

OLIGODACTYLY

Having fewer than normal digits.

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Niswander, L. Pattern formation: old models out on a limb. Nat Rev Genet 4, 133–143 (2003). https://doi.org/10.1038/nrg1001

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