Coincidental null mutation of Csf2rα in a colony of PI3Kγ-/- mice causes alveolar macrophage deficiency and fatal respiratory viral infection

PI-3-kinases have been identified as key signaling proteins involved in many basic biological processes in health and disease. Transgenic animals have been essential tools to study the underlying molecular mechanisms in this context and have therefore been widely used to elucidate the role of these factors in many different settings. More specifically, PI3Kγ, a subunit highly expressed in the hematopoietic system, has been implicated to play an important role in many inflammatory diseases as well as cancer. Here we report identification of multiple additional previously unknown mutations in the genome of a widely used PI3Kγ-deficient mouse colony. These include a STOP-mutation in the GM-CSFRα chain leading to a complete and specific deficiency in GM-CSF signaling. PI3Kγ-deficient animals consequently lacked alveolar macrophages and succumbed rapidly to influenza virus infection. Furthermore, PI3Kγ-deficient mice carried an additional mutation that affects Mucin 2 (Muc2) transcripts. This protein is strongly involved in the regulation of colorectal cancer and indeed conflicting reports have indicated that PI3Kγ-deficient animals spontaneously develop colorectal tumors. Thus, we uncover previously unknown confounding factors present in a strain of PI3Kγ-deficient mice leading to additional deficiencies in important signaling pathways with potentially wide-ranging implications for the interpretation of previous studies. By separating the mutations, we established unique Csf2ra-/- mouse model that allows study the role of cell intrinsic GM-CSF receptor signaling in vivo without confounding variables introduced by defective IL-5 receptor and IL-3 receptor signaling in mice lacking the common β chain (Csf2rb).