UNIVERSITY OF WISCONSIN SYSTEM
Limb deformity is one of the leading congenital disorders and the genetic mechanism underlying a vast majority of these cases remain unknown. Limb is also a prominent organ in the studies of organ regeneration. Strong evidence suggests that limbs regenerate in urodele due to their ability to restart the same molecular program that operates during limb formation. It is postulated that a full understanding of the normal program of limb development will assist genetic engineering to allow limbs to re-grow in non-regenerative limbs in higher tetrapods. The ultimate objective of this study is to understand vertebrate limb formation. In the past few years, the debate on the mechanisms of limb bud outgrowth and patterning has intensified as emerging molecular genetic evidence challenges a long-standing model (the Progress Zone model). At the center of the debate is the role of Fibroblast Growth Factors (FGFs). Genetic inactivation of Fgfs leads to loss or shortened limbs, mimicking birth defects. However, the mechanism of FGF function remains disputed. Our current experiments are aimed at addressing whether FGFs act by controlling growth and differentiation of limb progenitors, and/or instructing the shape of skeletal elements. Experiments proposed in the supplement will allow us to follow up unexpected and important findings from two of the three proposed Aims in the parent grant. We expect that findings from these studies will advance our understanding of limb-related birth defects and molecular programs underlying limb regeneration.