Abstract

Vertebrate limb outgrowth is driven by a positive feedback loop that involves Sonic hedgehog (Shh) and Gremlin1 (Grem1) in the posterior limb bud mesenchyme and Fibroblast growth factors (Fgfs) in the overlying epithelium. Proper spatio-temporal control of these signaling activities is required to avoid limb malformations such as polydactyly. Here we show that, in Tbx2-deficient hindlimbs, Shh/Fgf4 signaling is prolonged, resulting in increased limb bud size and duplication of digit 4. In turn, limb-specific Tbx2 overexpression leads to premature termination of this signaling loop with smaller limbs and reduced digit number as phenotypic manifestation. We show that Tbx2 directly represses Grem1 in distal regions of the posterior limb mesenchyme allowing Bone morphogenetic protein (Bmp) signaling to abrogate Fgf4/9/17 expression in the overlying epithelium. Since Tbx2 itself is a target of Bmp signaling, our data identify a growth-inhibiting positive feedback loop (Bmp/Tbx2/Grem1). We propose that proliferative expansion of Tbx2-expressing cells mediates self-termination of limb bud outgrowth due to their refractoriness to Grem1 induction.

Highlights

  • The condition of having more than the normal number of toes and/or fingers is the most frequent form of limb malformation in humans with an incidence of 1:500

  • Because apical ectodermal ridge (AER) expression of Fgf4 is mediated by inhibition of Bone morphogenetic protein (Bmp) signaling by the secreted Bmp antagonist Gremlin 1 (Grem1) [12,13], we explored the possibility of Grem1 regulation by Tbx2

  • Together our results strongly suggest that Tbx2 terminates Fgf4/Sonic hedgehog (Shh) signaling in the posterior limb bud by direct repression of Grem1

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Summary

Introduction

The condition of having more than the normal number of toes and/or fingers is the most frequent form of limb malformation in humans with an incidence of 1:500. Elucidation of the genetic, molecular and cellular changes that underlie polydactyly (as well as other limb defects) in humans has greatly benefitted from the analysis of normal limb development, and of the consequences of altered gene functions in suitable animal models such as the chicken and the mouse [1]. All of these studies unraveled that proper establishment and elaboration of the two main limb axes during development is crucial for setting up a correct number and identity of digits. In the limb primordium two signaling centers control the morphogenesis along these limb axes

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