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.
Center for Human Molecular Genetics, Munroe-Meyer Institute, Omaha, Nebraska 68198-5455, USA. ckappen@uncm.edu
Claudia
C
Kappen
Maria Alice
MA
Mello
Richard H
RH
Finnell
J Michael
JM
Salbaum
D000818:Animals; D019521:Body Patterning / Q000187:drug effects*; D002356:Cartilage / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D005260:Female; D005801:Genes, Homeobox / Q000502:physiology; D006652:Histological Techniques; D017403:In Situ Hybridization; D002955:Leucovorin / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012863:Skeleton
D002955:Leucovorin