A Hypomorphic Allele of Aryl Hydrocarbon Receptor-Associated Protein-9 Produces a Phenocopy of the Ahr-Null Mouse

Abstract

The aryl hydrocarbon receptor-associated protein-9 (ARA9) is a chaperone of the aryl hydrocarbon receptor (AHR). The AHR has been shown to play a late developmental role in the normal closure of a fetal hepatovascular shunt known as the ductus venosus (DV). Given that Ara9-null mice display early embryonic lethality, we generated a hypomorphic Ara9 allele (designated Ara9 fxneo ) that displays reduced ARA9 protein expression. In an effort to demonstrate the role of ARA9 protein in AHR-mediated DV closure, we used combinations of Ara9 wild-type [Ara9(ϩ/ϩ)], null [Ara9(Ϫ/Ϫ)], and hypomorphic [Ara9(fxneo/fxneo)] alleles to produce mice with a graded expression of the ARA9 protein. Liver perfusion studies demonstrated that although none of the Ara9(ϩ/ϩ) mice displayed a patent DV, the shunt was observed in 10% of the Ara9(ϩ/fxneo) mice, 55% of the Ara9(ϩ/Ϫ) mice, and 83% of the Ara9(fxneo/fxneo) mice. That expression level of ARA9 correlates with the frequency of a phenocopy of the Ahr-null allele supports the conclusion that the ARA9 protein is essential for AHR signaling during development.

Mice with Inactivation of Aryl Hydrocarbon Receptor-Interacting Protein (Aip) Display Complete Penetrance of Pituitary Adenomas with Aberrant ARNT Expression

“…18 In our study, Aip ϩ/Ϫ mice had the same or even slightly increased relative liver weight compared with WT littermates ( Figure 5). The reason for the discrepancy between these studies can be differences in the placement of the germ line mutation to produce the Aip inactivation or possibly the different C57BL substrains used for inbreeding.…”

“…In addition, most mice with reduced Aip expression showed failure of liver vein inclusion resulting in reduced liver size. 17,18 However, possible tumor predisposition was not approached in either study.Here we report a novel conventional Aip knockout mouse, which models the tumor susceptibility caused by human AIP germline mutations. We show that Aip ϩ/Ϫ mice are extremely prone to pituitary tumors, in particular GH secreting adenomas.…”

“…In addition, most mice with reduced Aip expression showed failure of liver vein inclusion resulting in reduced liver size. 17,18 However, possible tumor predisposition was not approached in either study.…”

The Aryl Hydrocarbon Receptor-interacting Protein (AIP) Is Required for Dioxin-induced Hepatotoxicity but Not for the Induction of the Cyp1a1 and Cyp1a2 Genes

“…1A) (24). To excise the neomycin resistance cassette (Neo), the Aip fxneo/ϩ mice were crossed to Flp ROSA26S mice (a Flp recombinase-expressing strain; Gt(ROSA)26Sor tm1(FLP1)Dym , The Jackson Laboratory, Bar Harbor, ME) (26,27).…”

“…Because Ahr null mice display normal heart development, we concluded that AIP plays an essential role in cardiovascular development in a manner that is independent of its role in AHR signaling (8,23). To overcome the embryonic lethality due to global Aip loss, we generated a hypomorphic Aip mouse model (designated Aip fxneo/fxneo ), which expressed ϳ10% AIP protein as compared with wild-type mice (24). The Aip fxneo/fxneo mice did not show heart defects nor significant embryonic lethality, yet they did display a high incidence of patent DV, similar to Ahr mutant mice and the Arnt mutant mice (8 -12, 24).…”