Molecular and physiological functions of LRIG proteins and netrin-1 in health and disease

Sammanfattning: The leucine-rich repeats and immunoglobulin-like domains (LRIG) gene family has three members, LRIG1, LRIG2, and LRIG3, that encode three structurally similar transmembrane proteins. LRIG1 is a receptor tyrosine kinase regulator, tumor suppressor, and stem cell marker in the skin, intestine, and brain. LRIG2 and LRIG3 have been less studied but shown to interact with LRIG1. The different roles and mechanisms of action of LRIG proteins have not yet been fully elucidated. In Caenorhabditis elegans (C. elegans), the LRIG homolog SMA-10 regulates bone morphogenetic protein (BMP) signaling; however, this function has not been demonstrated for mammalian LRIG proteins. In mice, the gene encoding the neurodevelopmental guidance cue netrin-1, Ntn1, interacts with Lrig3 in inner ear development. The physical interactions between LRIG proteins and other proteins are mostly unknown. Here, we describe an LRIG1-centered protein interaction network that regulates growth factor receptor levels. The LRIG1 interactome comprised LRIG2 and LRIG3 as well as many unanticipated proteins. An unbiased pathological examination of female mice with different Lrig3 genotypes (homozygous, heterozygous, or knockout) revealed a reduced incidence of spontaneous fatty liver and lymphocytic hyperplasia of the spleen in Lrig3-null mice. Female Lrig3-null mice also had a lower incidence of microvesicular cytoplasm in the liver after eight weeks on a high-fat diet. To further explore the molecular and physiological functions of LRIG proteins, we generated Lrig-null (Lrig1-/-;Lrig2-/-;Lrig3-/-) mouse embryonic fibroblasts (MEFs), which displayed a deficiency in adipogenesis caused by impaired BMP signaling. LRIG1 and LRIG3, but not LRIG2, sensitized cells to BMP and rescued the adipogenesis deficiency in Lrig-null MEFs. In C. elegans, the LRIG homolog sma-10 was needed for proper lipid accumulation. By analyzing data from the UK Biobank and GENiAL cohort, we found that certain LRIG1 gene variants were associated with a higher body mass index (BMI) yet protected against type 2 diabetes. This effect was probably mediated by altered adipocyte morphology. CRISPR/Cas9-mediated ablation of Ntn1 revealed that the BMP-promoting function of LRIG1 and LRIG3 was opposed by netrin-1, which functioned as an inhibitor of BMP signaling via its receptor neogenin.In summary, the present thesis describes a novel LRIG protein interaction network, the regulation of BMP signaling by LRIG proteins and netrin-1, and an important function of LRIG proteins in regulating fat metabolism with implications for human metabolic health.