Isl1Cre reveals a common Bmp pathway in heart and limb development

Development. 2006 Apr;133(8):1575-85. doi: 10.1242/dev.02322.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Base Sequence
  • Bone Morphogenetic Protein Receptors, Type I / genetics
  • Bone Morphogenetic Proteins / physiology*
  • Down-Regulation / physiology
  • Extremities / embryology*
  • Heart / embryology*
  • Heart Defects, Congenital / genetics
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / physiology*
  • LIM-Homeodomain Proteins
  • Mice
  • Mice, Knockout
  • Mice, Mutant Strains
  • Molecular Sequence Data
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology*
  • Phenotype
  • Promoter Regions, Genetic
  • Signal Transduction / genetics*
  • T-Box Domain Proteins / genetics
  • Transcription Factors

Substances

  • Bone Morphogenetic Proteins
  • Homeodomain Proteins
  • LIM-Homeodomain Proteins
  • Nerve Tissue Proteins
  • T-Box Domain Proteins
  • Tbx3 protein, mouse
  • Transcription Factors
  • insulin gene enhancer binding protein Isl-1
  • Bmpr1a protein, mouse
  • Bone Morphogenetic Protein Receptors, Type I