An Fgf/Gremlin inhibitory feedback loop triggers termination of limb bud outgrowth

Body size: when enough is enough The question of how a tissue grows to a certain size and knows when to stop remains a major mystery of biology. It is a phenomenon seen not only in body formation, but also in organs such as the liver when regeneration is allowed to occur. Many ideas have been proposed to explain how a tissue senses the limit of size, and few have been supported by experimental evidence. Jamie Verheyden and Xin Sun have discovered a new principle for control of organ size. In a study of the termination of signalling factors controlling growth and expansion in the mouse limb bud, a combination of mutations revealed an inhibitory loop whereby fibroblast growth factor (Fgf) signalling represses Gremlin1 expression, these two factors being key positive signals in limb bud outgrowth. This inhibitory loop is triggered by a positive Fgf/Shh loop. This model differs from earlier published models, and may have implications far beyond limb development, for size control in other organs, in evolution, and in limb regeneration.