AUTHOR=Menon Manoj B. , Yakovleva Tatiana , Ronkina Natalia , Suwandi Abdulhadi , Odak Ivan , Dhamija Sonam , Sandrock Inga , Hansmann Florian , Baumgärtner Wolfgang , Förster Reinhold , Kotlyarov Alexey , Gaestel Matthias 

TITLE=Lyz2-Cre-Mediated Genetic Deletion of Septin7 Reveals a Role of Septins in Macrophage Cytokinesis and Kras-Driven Tumorigenesis

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=9

YEAR=2022

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.795798

DOI=10.3389/fcell.2021.795798

ISSN=2296-634X

ABSTRACT=<p>By crossing <italic>septin7</italic>-floxed mice with <italic>Lyz2</italic>-Cre mice carrying the Cre recombinase inserted in the Lysozyme-M (<italic>Lyz2</italic>) gene locus we aimed the specific deletion of septin7 in myeloid cells, such as monocytes, macrophages and granulocytes. <italic>Septin7</italic><sup><italic>flox/flox</italic></sup>:<italic>Lyz2-</italic>Cre mice show no alterations in the myeloid compartment. <italic>Septin7</italic>-deleted macrophages (BMDMs) were isolated and analyzed. The lack of Septin7 expression was confirmed and a constitutive double-nucleation was detected in Septin7-deficient BMDMs indicating a defect in macrophage cytokinesis. However, phagocytic function of macrophages as judged by uptake of labelled <italic>E. coli</italic> particles and LPS-stimulated macrophage activation as judged by induction of TNF mRNA expression and TNF secretion were not compromised. In addition to myeloid cells, Lyz2-Cre is also active in type II pneumocytes (AT2 cells). We monitored lung adenocarcinoma formation in these mice by crossing them with the conditional knock-in <italic>Kras</italic>-LSL-G12D allele. Interestingly, we found that control mice without septin7 depletion die after 3–5 weeks, while the Septin7-deficient animals survived 11 weeks or even longer. Control mice sacrificed in the age of 4 weeks display a bronchiolo-alveolar hyperplasia with multiple adenomas, whereas the Septin7-deficient animals of the same age are normal or show only a weak multifocal brochiolo-alveolar hyperplasia. Our findings indicate an essential role of Septin7 in macrophage cytokinesis but not in macrophage function. Furthermore, septin7 seems absolutely essential for oncogenic <italic>Kras</italic>-driven lung tumorigenesis making it a potential target for anti-tumor interventions.</p>