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

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Abstract

LIMB development depends on signals from the apical ectodermal ridge and underlying mesenchyme1,2. Fibroblast growth factor (FGF) can replace the ridge3,4 and, because Fgf4RNA is localized to the mouse posterior ridge5, we proposed that FGF4 is the endogenous ridge signal3. Ridge signals control limb outgrowth and maintain the zone of polarizing activity (ZPA) at the limb posterior margin6, which is important in limb patterning: a ZPA graft to limb anterior mesenchyme causes cell respecification and mirror-image duplications1,2. Sonic hedgehog (SHH7,8) has polar-izing activity, and Shh RNA. co-localizes with ZPA activity, suggesting SHH is the endogenous polarizing signal7. We have investigated the molecular regulation of Fgf4 and Shh expression. We report here that Fgf4 expression in the ridge can be regulated byshh-expressing cells. Moreover, Shh expression in mesenchyme can be activated by FGF4 in combination with retinoic acid. Once induced, Shhexpression can be maintained by FGF4 alone, thus establishing a positive feedback loop between ZPA and ridge.

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Authors and Affiliations

  1. Department of Anatomy and Program in Developmental Biology, School of Medicine, University of California at San Francisco, San Francisco, California, 94143-0452, USA

    Lee Niswander & Gail R. Martin

  2. Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York, 10021, USA

    Lee Niswander & Susan Jeffrey

  3. Department of Anatomy and Developmental Biology, University College and Middlesex School of Medicine, Windeyer Building, Cleveland Street, London, W1P 6DB, UK

    Cheryll Tickle

Authors
  1. Lee Niswander
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  2. Susan Jeffrey
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  3. Gail R. Martin
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  4. Cheryll Tickle
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Niswander, L., Jeffrey, S., Martin, G. et al. A positive feedback loop coordinates growth and patterning in the vertebrate limb. Nature 371, 609–612 (1994). https://doi.org/10.1038/371609a0

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