Regulation of limb patterning by extracellular microfibrils

To elucidate the contribution of the extracellular microfibril-elastic fibe r network to vertebrate organogenesis, we generated fibrillin 2 (Fbn2)-null mice by gene targeting and identified a limb-patterning defect in the form of bilateral syndactyly. Digit fusion involves both soft and hard tissues, and is associated with reduced apoptosis at affected sites. Two lines of e vidence suggest that syndactily is primarily due to defective mesenchyme di fferentiation, rather than reduced apoptosis of interdigital tissue. First, fusion occurs before appearance of interdigital cell death; second, interd igital tissues having incomplete separation fail to respond to apoptotic cl ues from im-planted BMP-4 beads. Syndactyly is associated with a disorganiz ed matrix, but with normal BMP gene expression. On the other hand, mice dou ble heterozygous for null Fbn2 and Bmp7 alleles display the combined digit phenotype of both nullizygotes. Together, these results imply functional in teraction between Fbn2-rich microfibrils and BMP-7 signaling. As such, they uncover an unexpected relationship between the insoluble matrix and solubl e factors during limb patterning. We also demonstrate that the Fbn2-null mu tation is allelic to the recessive shaker-with-syndactyly (sy) locus on chr omosome 18.