Isl1Cre reveals a common Bmp pathway in heart and limb development

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.

β-Catenin directly regulates Islet1 expression in cardiovascular progenitors and is required for multiple aspects of cardiogenesis

“…With the exception of the epicardium, regions where ␤-catenin signaling was active during cardiogenesis were overlapping with Isl1 expression or Isl1-derived lineages (4). We therefore ablated ␤-catenin by using an Isl1-Cre generated in our laboratory (19,20). Isl1-Cre;␤-catenin mutants were embryonic-lethal.…”

“…Floxed ␤-catenin mice were obtained from the laboratory of Rolf Kemler (45). Isl1-Cre mice were created in our laboratory by a Cre knockin into the endogenous Isl1 locus, replacing the endogenous Isl1 ATG (19,20). Homozygous floxed ␤-catenin mice were crossed with Protamine-Cre mice (46) to generate ␤-catenin ϩ/Ϫ mice, which were then crossed with Isl1-Cre mice to produce doubly heterozygous Isl1-Cre;␤-catenin ϩ/Ϫ mice.…”

“…The early expression of Isl1-Cre in cardiogenic progenitors, and in early pharyngeal endoderm (19,20), a cardiac-inducing tissue, provided us with an opportunity to examine the requirement for ␤-catenin in these tissues during early cardiogenesis.…”

Histone Deacetylase 3 Coordinates Deacetylase-independent Epigenetic Silencing of Transforming Growth Factor-β1 (TGF-β1) to Orchestrate Second Heart Field Development

“…To determine the function of HDAC3 in the second heart field, we deleted HDAC3 in the second heart field progenitor cells using two Cre lines, Isl1-Cre (Hdac3 Isl1KO ) (Fig. 1, A-C) and Mef2C-Cre (Hdac3 Mef2CKO ) (7,50). Hdac3…”

Pbx1 activates Fgf10 in the mesenchyme of developing lungs

“…f/f (Koss et al, 2012) and Islet1Cre (Cai et al, 2003;Yang et al, 2006) mice have been described previously. The date of observing a vaginal plug was set as E0.5, and embryonic development was confirmed by ultrasonography before sacrificing pregnant mice (Chang et al, 2003).…”