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.
Yang
Lei
L
Skaggs School of Pharmacy, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Cai
Chen-Leng
CL
Lin
Lizhu
L
Qyang
Yibing
Y
Chung
Christine
C
Monteiro
Rui M
RM
Mummery
Christine L
CL
Fishman
Glenn I
GI
Cogen
Anna
A
Evans
Sylvia
S
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