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Ifitm1 – unique function to be determined?

For the Interferon induced transmembrane protein 1 (Ifitm1, fragilis2, mil-2, 9-27, Leu-13), a 17kDa protein, several putative functions have been suggested. These were either based on indirect experimental evidence or inferred from sequence or gene expression data. Among these is the idea of Ifitm1 as being regulated during an antitumoral, antiviral or antibacterial immune response. Several comparative gene expression analyses, mainly in human tissues, revealed alterations of Ifitm1 expression in various cancer types, including breast cancer, colorectal tumors, gastric cancer, esophageal cancer, ovarian carcinoma, head and neck cancer, pancreatic cancer and lung cancer, as well as in a form of schizophrenia and in Epstein-Barr virus related diseases. In addition, Ifitm1 was described as a marker for the prognosis of chronic myeloid leukemia. Another suggested function for Ifitm1 is its requirement for primordial germ cell (PGC) specification and migration and as a downstream target of the Wnt/β-catenin signalling pathway.

To assess the in vivo function of Ifitm1 Ingeborgy Klymiuk from the HelmholtzZentrum Munich and her colleagues used a targeted mutagenesis approach that replaced the coding region of the Ifitm1 gene with a lacZ reporter gene in the mouse.

Besides detailed analysis of the loss-of-function allele Ifitm1tm1IEG (Mendalian ratios, sperm motility and fertility – normal, somites and skeleton – no abnormalities, leukocyte numbers – unchanged, challenging infection with Listeria monocytogenes – no differences in the number of CFU) mutant mice were systemically phenotyped in the German Mouse Clinic.

Modest changes is systemic phenotpying

Modest but statistically significant changes between mutant and wildtype mice were identified in the neurological (modest reduction in rotarod latency), energy metabolism (trend towards increased mean oxygen consumption in female mutant mice), clinical chemistry (slight increase in specific hematological parameters of female mutant mice), immunology (slightly reduced frequencies of granulocytes and CD44 expressing T-cells in mutant mice), allergy (trend towards increased plasma IgE levels in mutant mice), steroid metabolism (slightly decreased corticosterone concentrations in female mutant mice, and high variance in testosterone concentrations in male mutant mice), and pathology (slight increase in liver weights normalized to body weights) screens. No significant differences were found in the dysmorphology, behaviour, nociception, eye, and lung function screens.

The scientists also analyzed IFITM1 expression in human lung tissue by immunohistochemistry and found IFITM1 expression in columnar- and basal cells of the bronchial epithelium. In contrast to the expression in mice, human IFITM1 expression was predominantly detected in the basal cell layer rather than in the predominantly CYTOKERATIN-7 (CK7) expressing columnar cells. IFITM1 expression was detected in non-neoplastic alveolar and bronchial epithelium of the normal human lung. Interestingly, strong IFITM1 overexpression was found in the tumor epithelia cells of human squamous cell carcinomas as well as in adenocarcinomas of NSCLC patient samples.

Based on the findings the suspected functions for Ifitm1 as well as other genes of the Ifitm gene family could not be confirmed by targeted in vivo studies. Here, the comprehensive description of Ifitm1 gene expression patterns in mouse embryos and adult organs now provides a basis for more systematic and targeted approaches to uncover unique Ifitm1 functions in vivo. Of special interest might be the role of Ifitm1 for lung cancer development and treatment. The results underline the importance of targeted functional in vivo studies since the hypothesized functions of Ifitm1 were not confirmed by the experiments.

 

In vivo functional requirement of the mouse Ifitm1 gene for germ cell development, interferon mediated immune response and somitogenesis”, Klymiuk et al., PLOS one, Oct 2012 | Vol 7 | Issue 10 | e44609