Limb Development Takes a Measured Step Toward Systems Analysis

Susan Mackem^* and Mark Lewandoski^*

Cancer and Developmental Biology Laboratory, National Cancer Institute, NCI-Frederick, Frederick, MD 21702, USA.

Abstract: Growth and patterning of the embryonic vertebrate limb is regulated by feedback loops signaling between the epithelium and mesenchyme of the limb bud. Fibroblast growth factor (FGF) signaling from the epithelium regulates Sonic hedgehog (Shh) expression in the mesenchyme. In turn, SHH activity maintains the expression of Gremlin1, which encodes a bone morphogenetic protein (BMP) antagonist; the interaction between BMP and Gremlin1 regulates Fgf gene expression. A computational model using data from complex genetic analysis and quantitative measurements of gene induction kinetics demonstrates that limb development is robust and thus buffered against certain mutational alterations and epigenetic changes because of these feedback loops.

* Corresponding authors. E-mail, mackems{at}mail.nih.gov (S.M.); mlewandoski{at}mail.ncifcrf.gov (M.L.).

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