Isl1Cre reveals a common Bmp pathway in heart and limb development.
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.
Skaggs School of Pharmacy, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Lei
L
Yang
Chen-Leng
CL
Cai
Lizhu
L
Lin
Yibing
Y
Qyang
Christine
C
Chung
Rui M
RM
Monteiro
Christine L
CL
Mummery
Glenn I
GI
Fishman
Anna
A
Cogen
Sylvia
S
Evans
D000818:Animals; D001483:Base Sequence; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D015536:Down-Regulation / Q000502:physiology; D005121:Extremities / Q000196:embryology*; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D060850:LIM-Homeodomain Proteins; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000235:genetics*; D020825:T-Box Domain Proteins / Q000235:genetics; D014157:Transcription Factors
D019485:Bone Morphogenetic Proteins; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D009419:Nerve Tissue Proteins; D020825:T-Box Domain Proteins; C491460:Tbx3 protein, mouse; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I