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First published online March 23, 2006
doi: 10.1242/10.1242/dev.02322
1 Skaggs School of Pharmacy, University of California, San Diego, 9500 Gilman
Drive, La Jolla, CA 92093, USA.
2 Department of Medicine, University of California, San Diego, 9500 Gilman
Drive, La Jolla, CA 92093, USA.
3 Cardiovascular Research Center, Massachusetts General Hospital, Harvard
Medical School, Boston, 185 Cambridge Street, MA 02114, USA.
4 Hubrecht Laboratory (Netherlands Institute for Developmental Biology),
Utrecht, The Netherlands.
5 Interuniversity Cardiology Institute of the Netherlands, Utrecht, The
Netherlands.
6 Leon H. Charney Division of Cardiology, New York University School of
Medicine, New York, NY 10016, USA.
* Author for correspondence (e-mail: syevans{at}ucsd.edu)
Accepted 13 February 2006
A number of human congenital disorders present with both heart and limb defects, consistent with common genetic pathways. We have recently shown that the LIM homeodomain transcription factor islet 1 (Isl1) marks a subset of cardiac progenitors. Here, we perform lineage studies with an Isl1Cre mouse line to demonstrate that Isl1 also marks a subset of limb progenitors. In both cardiac and limb progenitors, Isl1 expression is downregulated as progenitors migrate in to form either heart or limb. To investigate common heart-limb pathways in Isl1-expressing progenitors, we ablated the Type I Bmp receptor, Bmpr1a utilizing Isl1Cre/+. Analysis of consequent heart and limb phenotypes has revealed novel requirements for Bmp signaling. Additionally, we find that Bmp signaling in Isl1-expressing progenitors is required for expression of T-box transcription factors Tbx2 and Tbx3 in heart and limb. Tbx3 is required for heart and limb formation, and is mutated in ulnar-mammary syndrome. We provide evidence that the Tbx3 promoter is directly regulated by Bmp Smads in vivo.
Key words: Isl1, Bmp, Tbx2, Tbx3, Heart, Hindlimb
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