Dr. Thomas Lufkin and his colleagues at Mount Sinai School of Medicine have discovered that Dlx genes, the mammalian counterparts of the fruit fly Distal-less (Dll) gene, are required for normal mammalian limb development. The researchers also show that deficiencies in two of these Dlx genes may underlie a devastating human developmental disorder. The report will be published in the May 1 issue of Genes & Development.
Although human limbs appear markedly different from fruit fly antennae, this study suggests that homologous genes are responsible for the development of these seemingly divergent structures. The Dll/Dlx gene family was originally identified in the Drosophila fruit fly, where it is required for proximal-distal axis formation in the legs and antennae. Members of the Dll/Dlx gene family encode transcription factors: DNA-binding proteins that regulate the expression of other genes. Dll/Dlx family members are involved in the limb formation of a variety of vertebrate species. This work by Dr. Lufkins research team extends the known range of Dlx function in limb formation to mammals.
There are six mammalian Dlx genes (Dlx1-6); the human Dlx5 and Dlx6 genes are located on an area of chromosome 7 which is often disrupted in people with split-hand/split-foot malformation (SHFM). SHFM, or lobster-claw deformity, is a congenital disorder characterized by the fusion of the central digits of the hands and feet, resulting in claw-like extremities.
Dr. Lufkins team set out to determine if Dlx5 and 6 were, in fact, the genes responsible for SHFM.
Mice have been historically used to model human disease, and SHFM is no exception. Previous research groups made transgenic mice deficient in Dlx1, 2, 1 and 2, or 5, but none of these mutant mice displayed abnormalities in limb formation. Dr. Lufkin and colleagues took this to suggest that perhaps some of the Dlx genes have (at least partially) overlapping functions. With this in mind, the s
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Contact: Nora Poppito
poppito@cshl.org
Cold Spring Harbor Laboratory
30-Apr-2002