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Related Experiment Videos

A positive feedback loop coordinates growth and patterning in the vertebrate limb

L Niswander1, S Jeffrey, G R Martin

  • 1Department of Anatomy, School of Medicine, University of California at San Francisco 94143-0452.

Nature
|October 13, 1994
PubMed
Summary

Fibroblast growth factor (FGF) and Sonic hedgehog (SHH) signaling pathways regulate limb development. FGF4 and SHH establish a positive feedback loop, crucial for limb outgrowth and patterning.

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Area of Science:

  • Developmental Biology
  • Molecular Biology
  • Genetics

Background:

  • Limb development is orchestrated by signals from the apical ectodermal ridge (AER) and underlying mesenchyme.
  • Fibroblast growth factor (FGF) can substitute for AER function, with Fgf4 RNA localized to the posterior AER, suggesting FGF4 as an endogenous ridge signal.
  • The zone of polarizing activity (ZPA) at the posterior limb margin is vital for patterning, with Sonic hedgehog (SHH) identified as a key polarizing signal.

Purpose of the Study:

  • To investigate the molecular regulation of Fgf4 and Shh gene expression during limb development.
  • To elucidate the signaling interactions between the AER and ZPA in limb patterning.
  • To determine the role of FGF4 and SHH in establishing a feedback loop for limb outgrowth and patterning.

Main Methods:

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  • Analysis of gene expression patterns (Fgf4 and Shh RNA localization).
  • Investigating the effects of Shh-expressing cells on Fgf4 expression in the AER.
  • Examining the induction and maintenance of Shh expression by FGF4 and retinoic acid in the mesenchyme.

Main Results:

  • Shh-expressing cells were found to regulate Fgf4 expression in the apical ectodermal ridge.
  • FGF4, in combination with retinoic acid, can activate Shh expression in the mesenchyme.
  • FGF4 alone can maintain Shh expression, indicating a positive feedback loop between the ZPA and AER.

Conclusions:

  • A reciprocal signaling loop exists between the AER (FGF4) and ZPA (SHH) during limb development.
  • This FGF4-SHH feedback mechanism is essential for regulating limb outgrowth and anteroposterior patterning.
  • Understanding these molecular interactions provides insights into the genetic control of vertebrate limb formation.