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.
Bibliographical noteFunding Information:
We apologize for the impossibility of citing all relevant references, due to space constraints. We thank Phil Beachy for providing the Shh −/− mice, Richard Harland for providing the mouse Gremlin probe, Lee Niswander and Cliff Tabin for RCAS constructs, Juan Hurlé, Steve O'Gorman, Licia Selleri, and Miguel Torres for sharing unpublished data, Dirk Büscher and Ana Tavares for insightful discussions, and Lorraine Hooks for help in preparing the manuscript. V. Z. is supported by grants from the Italian Association for Cancer Research (AIRC) and from Telethon. This work was supported by grants from the G. Harold and Leila Y. Mathers Charitable Foundation and the NSF to J. C. I. B., who is a Pew Scholar.
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology