Folate modulates Hox gene-controlled skeletal phenotypes

Hox genes are well-known regulators of pattern formation and cell differentiation in the developing vertebrate skeleton. Although skeletal variations are not uncommon in humans few mutations in human HOX genes have been described. If such mutations are compatible with life, there may be physiological modifiers for the manifestation of Hox gene-controlled phenotypes, masking underlying mutations. Here we present evidence that the essential nutrient folate modulates genetically induced skeletal defects in Hoxd4 transgenic mice. We also show that chondrocytes require folate for growth and differentiation and that they express folate transport genes, providing evidence for a direct effect of folate on skeletal cells. To our knowledge, this is the first report of nutritional influence on Hox gene-controlled phenotypes, and implicates gene-environment interactions as important modifiers of Hox gene function. Taken together, our results demonstrate a beneficial effect of folate on skeletal development that may also be relevant to disorders and variations of the human skeleton.