TY - JOUR
T1 - Regulation of limb patterning by extracellular microfibrils
AU - Arteaga-Solis, Emilio
AU - Gayraud, Barbara
AU - Lee, Sui Y.
AU - Shum, Lillian
AU - Sakai, Lynn
AU - Ramirez, Francesco
PY - 2001/7/23
Y1 - 2001/7/23
N2 - 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.
AB - 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.
KW - BMP
KW - Fibrillin
KW - Limb patterning
KW - Morphogenesis
KW - Syndactyly
UR - http://www.scopus.com/inward/record.url?scp=0035939667&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035939667&partnerID=8YFLogxK
U2 - 10.1083/jcb.200105046
DO - 10.1083/jcb.200105046
M3 - Article
C2 - 11470817
AN - SCOPUS:0035939667
SN - 0021-9525
VL - 154
SP - 275
EP - 281
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 2
ER -