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Published 23 July 2001. doi:10.1083/jcb.200105046
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© The Rockefeller University Press, 0021-9525/2001/7/275 $5.00
The Journal of Cell Biology, Volume 154, Number 2, July 23, 2001 275-282

Report

Regulation of limb patterning by extracellular microfibrils



Emilio Arteaga-Solis1, Barbara Gayraud1, Sui Y. Lee1, Lillian Shum2, Lynn Sakai3 and Francesco Ramirez1

1 Brookdale Center, Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine, New York, NY 10029
2 Craniofacial Development Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892
3 The Shriners Hospital for Children, Portland, OR 97201

Address correspondence to Francesco Ramirez, Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1020, New York, NY 10029. Tel.: (212) 241-1757. Fax: (212) 722-5999. E-mail: ramirf01{at}doc.mssm.edu

To elucidate the contribution of the extracellular microfibril–elastic fiber 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 evidence suggest that syndactily is primarily due to defective mesenchyme differentiation, rather than reduced apoptosis of interdigital tissue. First, fusion occurs before appearance of interdigital cell death; second, interdigital tissues having incomplete separation fail to respond to apoptotic clues from implanted BMP-4 beads. Syndactyly is associated with a disorganized matrix, but with normal BMP gene expression. On the other hand, mice double heterozygous for null Fbn2 and Bmp7 alleles display the combined digit phenotype of both nullizygotes. Together, these results imply functional interaction between Fbn2-rich microfibrils and BMP-7 signaling. As such, they uncover an unexpected relationship between the insoluble matrix and soluble factors during limb patterning. We also demonstrate that the Fbn2- null mutation is allelic to the recessive shaker-with-syndactyly (sy) locus on chromosome 18.

Key Words: BMP; fibrillin; limb patterning; morphogenesis; syndactyly


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