Isl1Cre reveals a common Bmp pathway in heart and limb development
Open accessAbstract
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.
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Critical morphogenic and oncogenic signaling pathways, including BMPs, Shh, TGF-β, FGFs, Wnt/β-catenin, and BRAF/MAPK, participate in TBX3 expression regulation, mostly at the transcriptional level.
“Thus, critical morphogenic and oncogenic signaling pathways, such as BMPs17, Shh18, TGF-β19, FGFs20, Wnt/β-catenin21, as well as BRAF/MAPK pathway, participate in TBX3 expression regulation, mostly at the transcriptional level12,15.”
From Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis (2024) · cites this paper as [17]
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“Notably, it has been shown that Tbx3 is a direct target of BMP Smads ( 43 ).”
BackgroundThe roles and regulation of TBX3 in development and disease
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“Thus, critical morphogenic and oncogenic signaling pathways, such as BMPs 17 , Shh 18 , TGF-β 19 , FGFs 20 , Wnt/ β -catenin 21 , as well as BRAF/MAPK pathway, participate in TBX3 expression regulation, mostly at the transcriptional level 12,15 .”
Background
- Authors
- Yang, L., Cai, C.-L., Lin, L., Qyang, Y., Chung, C., Monteiro, R. M., Mummery, C. L., Fishman, G. I., Cogen, A., & Evans, S.
- Affiliations
- University of California San Diego (US)
- Harvard University (US)
- Netherlands Heart Institute (NL)
- New York University (US)
- Corresponding author
- Evans, Sylvia
- ORCID
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2006-04-15
- Volume
- 133
- Issue
- 8
- Pages
- 1575-1585
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- PMC
- PMC5576437
- OpenAlex
- W2096999174
- Cited by
- 267
- References
- 2
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 17 · 2023: 11 · 2022: 13 · 2021: 16 · 2020: 17 · 2019: 17 · 2018: 14 · 2017: 15 · 2016: 10 · 2015: 9 · 2014: 14 · 2013: 19 · 2012: 18
- FWCI
- 6.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Development (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (submittedVersion)
- Funders
- National Institutes of Health (DP1OD006428)
- National Heart, Lung, and Blood Institute (R01HL074066, R01HL070867, DP1HL117649)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Developmental Biology › Congenital limb and hand anomalies
- Keywords
- Isl1, BMP signaling, BMPR1A, cardiac progenitor cells, heart development, limb development, TBX3, TBX2, Smad, ulnar-mammary syndrome, congenital heart disease, congenital limb anomalies, lineage tracing
- MeSH terms
- Animals, Base Sequence, Extremities, Heart, Heart Defects, Congenital, Mice, Mutant Strains, Molecular Sequence Data, Nerve Tissue Proteins, Phenotype, Promoter Regions, Genetic, Transcription Factors, Signal Transduction, Down-Regulation, Mice, Knockout, Homeodomain Proteins, Bone Morphogenetic Proteins, T-Box Domain Proteins, Mice, Bone Morphogenetic Protein Receptors, Type I, LIM-Homeodomain Proteins
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