Control of vertebrate limb outgrowth by the proximal factor Meis2 and distal antagonism of BMPs by Gremlin.
The mechanisms controlling growth and patterning along the proximal-distal axis of the vertebrate limb are yet to be understood. We show that restriction of expression of the homeobox gene Meis2 to proximal regions of the limb bud is essential for limb development, since ectopic Meis2 severely disrupts limb outgrowth. We also uncover an antagonistic relationship between the secreted factors Gremlin and BMPs required to maintain the Shh/FGF loop that regulates distal outgrowth. These proximal and distal factors have coordinated activities: Meis2 can repress distal genes, and Bmps and Hoxd genes restrict Meis2 expression to the proximal limb bud. Moreover, combinations of BMPs and AER factors are sufficient to distalize proximal limb cells. Our results unveil a novel set of proximal-distal regulatory interactions that establish and maintain outgrowth of the vertebrate limb.
Capdevila
J
J
Salk Institute for Biological Studies, Gene Expression Laboratory, La Jolla, California 92037, USA.
Tsukui
T
T
Rodríquez Esteban
C
C
Zappavigna
V
V
Izpisúa Belmonte
J C
JC
D000818:Animals; D019521:Body Patterning / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002642:Chick Embryo; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004475:Ectoderm / Q000166:cytology / Q000378:metabolism; D004627:Embryonic Induction; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005801:Genes, Homeobox / Q000235:genetics / Q000502:physiology; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D018878:Limb Buds / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D008863:Microspheres; D008954:Models, Biological; D008969:Molecular Sequence Data; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators; D014162:Transfection
D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; C486399:GREM1 protein, human; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C509239:SHH protein, human; D015534:Trans-Activators; C083400:PBX1 protein, human; D005346:Fibroblast Growth Factors