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Netrin-1 functions as a suppressor of bone morphogenetic protein (BMP) signaling
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.ORCID iD: 0000-0003-3502-5948
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Oncology Research Laboratory, NUS M31, Umeå, Sweden.ORCID iD: 0000-0001-6891-6996
2021 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 8585Article in journal (Refereed) Published
Abstract [en]

Netrin-1 is a secreted protein that is well known for its involvement in axonal guidance during embryonic development and as an enhancer of cancer cell metastasis. Despite extensive efforts, the molecular mechanisms behind many of the physiological functions of netrin-1 have remained elusive. Here, we show that netrin-1 functions as a suppressor of bone morphogenetic protein (BMP) signaling in various cellular systems, including a mutually inhibitory interaction with the BMP-promoting function of leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins. The BMP inhibitory function of netrin-1 in mouse embryonic fibroblasts was dependent on the netrin receptor neogenin, with the expression level regulated by both netrin-1 and LRIG proteins. Our results reveal a previously unrecognized function of netrin-1 that may help to explain several of the developmental, physiological, and cancer-promoting functions of netrins at the signal transduction level.

Place, publisher, year, edition, pages
Nature Publishing Group, 2021. Vol. 11, no 1, article id 8585
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-182911DOI: 10.1038/s41598-021-87949-7ISI: 000644194200021PubMedID: 33883596Scopus ID: 2-s2.0-85104705931OAI: oai:DiVA.org:umu-182911DiVA, id: diva2:1558198
Available from: 2021-05-28 Created: 2021-05-28 Last updated: 2022-09-15Bibliographically approved
In thesis
1. Molecular and physiological functions of LRIG proteins and netrin-1 in health and disease
Open this publication in new window or tab >>Molecular and physiological functions of LRIG proteins and netrin-1 in health and disease
2021 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2021. p. 68
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2150
Keywords
LRIG, Netrin-1, LRIG1, LRIG2, LRIG3, Type 2 diabetes
National Category
Cancer and Oncology Endocrinology and Diabetes Cell Biology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-186845 (URN)978-91-7855-621-2 (ISBN)978-91-7855-622-9 (ISBN)
Public defence
2021-09-17, Bergasalen, Norrlands Universitetssjukhus, Umeå, 13:00 (English)
Opponent
Supervisors
Note

The thesis will be defended via zoom link: https://umu.zoom.us/j/68144103623

Available from: 2021-08-27 Created: 2021-08-24 Last updated: 2022-09-09Bibliographically approved

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Abdullah Nasir, AhmadHerdenberg, CarlHedman, Håkan

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