A hypomorphic mutation of the gamma-1 adaptin gene (Ap1g1) causes inner ear, retina, thyroid, and testes abnormalities in mice

Abstract

Adaptor protein (AP) complexes function in the intracellular sorting and vesicular transport of membrane proteins. The clathrin-associated AP-1 complex functions at the trans-Golgi network and endosomes, and some forms of this complex are thought to mediate the sorting of proteins in plasma membranes of polarized epithelial cells. A null mutation of the mouse Ap1g1 gene, which encodes the gamma-1 subunit of the AP-1 complex, causes embryonic lethality when homozygous, indicating its critical importance in early development but precluding studies of its possible roles during later stages. Here, we describe our analyses of a new spontaneous mutation of Ap1g1 named “figure eight” (symbol fgt) and show that it is an in-frame deletion of 6 bp, which results in the elimination of two amino acids of the encoded protein. In contrast to Ap1g1−/− null mice, mice homozygous for the recessive fgt mutation are viable with adult survival similar to controls. Although Ap1g1 is ubiquitously expressed, the phenotype of Ap1g1fgt mutant mice is primarily restricted to abnormalities in sensory epithelial cells of the inner ear, pigmented epithelial cells of the retina, follicular epithelial cells of the thyroid gland, and the germinal epithelium of the testis, suggesting that impaired AP-1 sorting and targeting of membrane proteins in these polarized cells may underlie the observed pathologies. Ap1g1fgt mutant mice provide a new animal model to study the in vivo roles of gamma-1 adaptin and the AP-1 complex throughout development and to investigate factors that underlie its associated phenotypic abnormalities.

AP1G1 is involved in cetuximab-mediated downregulation of ASCT2-EGFR complex and sensitization of human head and neck squamous cell carcinoma cells to ROS-induced apoptosis

“…AP1G1 expression has been found to be high in some types of human cancers [38]. Although the biological significance of increased AP1G1 expression in cancer is not clear yet, AP1G1 is known to play a critical role in early development because a null mutation of AP1G1 was embryonic lethal when the mutation was homozygous [53]. Hundreds of proteins have been predicted to interact with AP1G1 [54], so it is not surprising that EGFR and ASCT2 are on the list.…”

Spontaneous Posterior Segment Vascular Disease Phenotype of a Mouse Model,rnv3, Is Dependent on theCrb1rd8Allele

“…Abnormal retinal vascularization, a pathologic condition in many vision-threatening diseases, can lead to serious consequences, including blindness. 5 - 8 , 14 Development of reproducible and reliable animal models of RNV has advanced our understanding of both the normal development and pathobiology of aberrant retinal vascularization. In this study, we describe robust, heritable mouse models of abnormal retinal vascularization, one of which is caused by a nucleotide deletion in the Crb1 gene that was previously described as the retinal degeneration 8 ( rd8 ) mutation.…”

“… 2 – 4 Development of reproducible and reliable animal models to study these vascular diseases has advanced our understanding of both the normal development and the pathophysiology of abnormal ocular blood vessel growth. 5 – 8 For example, we discovered the first retinal vascularization (RNV) phenotype in Vldlr -targeted null mutant mice and characterized this strain as a reproducible model of subretinal vascularization and choroidal anastomosis. 5 This model, made available through the JAX Eye Mutant Resource, has enabled numerous studies investigating the potential underlying mechanisms and treatments for wet AMD, RAP, and macular telangiectasia.…”

“… 5 This model, made available through the JAX Eye Mutant Resource, has enabled numerous studies investigating the potential underlying mechanisms and treatments for wet AMD, RAP, and macular telangiectasia. 9 – 14 The second reproducible model of retinal vascularization was discovered in the figure eight ( fgt ) model, where a mutation of the adaptor protein complex AP-1, gamma 1 subunit ( Ap1g1 ) gene 6 was identified. Ap1g1 fgt mutant mice develop early vascular lesions in the retina and provide a reliable animal model for studying factors that initiate retinal angiogenesis, subretinal vascularization, and choroidal vascular anastomosis formation.…”

“…Ap1g1 fgt mutant mice develop early vascular lesions in the retina and provide a reliable animal model for studying factors that initiate retinal angiogenesis, subretinal vascularization, and choroidal vascular anastomosis formation. 6 The third retinal vascular lesion model was identified in a B6;129 mixed background strain, which we named retinal vascularization 3 ( rnv3 , aka JR5558 7 or Nrv2 8 ).…”