Generation of a mouse with conditionally activated signaling through the BMP receptor, ALK2

Abstract

BMP signaling plays pleiotropic roles in various tissues. Transgenic mouse lines that overexpress BMP signaling in a tissue-specific manner would be beneficial; however, production of each tissue-specific transgenic mouse line is labor-intensive. Here, using a Cre-loxP system, we generated a conditionally overexpressing mouse line for BMP signaling through the type I receptor ALK2 (alternatively known as AVCRI, ActRI, or ActRIA). By mating this line with Cre-expression mouse lines, Cre-mediated recombination removes an intervening floxed lacZ expression cassette and thereby permits the expression of a constitutively active form of Alk2 (caAlk2) driven by a ubiquitous promoter, CAG. Tissue specificity of Cre recombination was monitored by a bicistronically expressed EGFP following Alk2 cDNA. Increased BMP signaling was confirmed by ectopic phosphorylation of SMAD1/5/8 in the areas where Cre recombination had occurred. The conditional overexpression system described here provides versatility in investigating gene functions in a tissue-specific manner without having to generate independent tissue-specific transgenic lines.

Constitutively Active ALK2 Receptor Mutants Require Type II Receptor Cooperation

“…These mice were bred to provide compound BmpRIIconditionally deficient and ActRIIa-globally deficient (Bmpr2 flox/flox : Acvr2a Ϫ/Ϫ ) mice. Conditional ALK2 Q207D transgenic (Tg) mice, also called CAG-Z-eGFP-caALK2 or caALK2 Tg mice, have been previously described (14,17). All mouse experiments were approved by the Massachusetts General Hospital Subcommittee on Research Animal Care and the Harvard Medical School Institutional Animal Care and Use Committee.…”

ACVR1 R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A

“…Another conditional-on transgenic mouse—Tg(CAG-LacZ,-ACVR1*,-EGFP)35–1Mis (27, 28)—has been used to model FOP (29) by using a constitutively active (and largely ligand-independent) artificial variant, ACVR1[Q207D] (30), to induce Smad1/5/8 signaling after Cre treatment. This mouse likely models only one aspect of FOP, that is, the HO process resulting from Smad1/5/8 signaling.…”

Insights from a rare genetic disorder of extra-skeletal bone formation, fibrodysplasia ossificans progressiva (FOP)

“…Conditional ACVR1/ALK2 knockout mouse studies have identified roles for ACVR1 in specific tissues and developmental processes. In order to investigate effects of ACVR1 gain of function during embryonic development in specific tissues, a conditionally regulated mouse model to express a constitutively active form of ACVR1 (caALK2) has also been developed [72].…”