Signaling by the transforming growth factor beta (TGF-beta) ligands occurs through different mechanisms of which the receptor-II/receptor-I mediated pathway is the most studied. Signals are conveyed through serine-threonine kinase receptors at the cell surface to specific intracellular mediators, the Smad proteins. Activation of Smad proteins results in their translocation to the nucleus and subsequent activation of gene expression. Mouse knockouts of genes encoding Smads have been generated by Tang et.al. using embryonic stem cells, to yield a phenotype showing disrupted TGF-b signaling by Smad proteins. This pathway includes ELF (a beta spectrin) in TGF-b signaling during early stages development. Homozygous ELF (elf-/-) exhibited a phenotype similar to heterozygous smad2+/- or smad3+/-.