Umeå University's logo

umu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
LRIG proteins regulate lipid metabolism via BMP signaling and affect the risk of type 2 diabetes
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.ORCID iD: 0000-0001-5824-6263
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.ORCID iD: 0000-0003-3502-5948
Show others and affiliations
2021 (English)In: Communications Biology, E-ISSN 2399-3642, Vol. 4, no 1, article id 90Article in journal (Refereed) Published
Abstract [en]

Leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins have been implicated as regulators of growth factor signaling; however, the possible redundancy among mammalian LRIG1, LRIG2, and LRIG3 has hindered detailed elucidation of their physiological functions. Here, we show that Lrig-null mouse embryonic fibroblasts (MEFs) are deficient in adipogenesis and bone morphogenetic protein (BMP) signaling. In contrast, transforming growth factor-beta (TGF-beta) and receptor tyrosine kinase (RTK) signaling appeared unaltered in Lrig-null cells. The BMP signaling defect was rescued by ectopic expression of LRIG1 or LRIG3 but not by expression of LRIG2. Caenorhabditis elegans with mutant LRIG/sma-10 variants also exhibited a lipid storage defect. Human LRIG1 variants were strongly associated with increased body mass index (BMI) yet protected against type 2 diabetes; these effects were likely mediated by altered adipocyte morphology. These results demonstrate that LRIG proteins function as evolutionarily conserved regulators of lipid metabolism and BMP signaling and have implications for human disease. Herdenberg et al. show that adipogenesis and BMP signaling are altered in mouse cells deficient in LRIG (Leucine-rich repeats and immunoglobulin-like domains) proteins. They find that mutant LRIG/sma-10 variant worms exhibit lipid storage defects and that human LRIG1 variants are associated with higher body mass index, yet protect against type 2 diabetes. This study suggests an evolutionarily conserved role of LRIG proteins for lipid metabolism and BMP signaling.

Place, publisher, year, edition, pages
Springer Nature, 2021. Vol. 4, no 1, article id 90
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-180823DOI: 10.1038/s42003-020-01613-wISI: 000613509200014PubMedID: 33469151Scopus ID: 2-s2.0-85099541477OAI: oai:DiVA.org:umu-180823DiVA, id: diva2:1531700
Available from: 2021-02-26 Created: 2021-02-26 Last updated: 2022-09-09Bibliographically 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

Open Access in DiVA

fulltext(1446 kB)175 downloads
File information
File name FULLTEXT01.pdfFile size 1446 kBChecksum SHA-512
effc03f6c90cd4d74e0617ae6b416e6917f2b1ec526c3f6b25307b5f8da07b1d7ee62e6ac10be5c6ec3fcf030ac7efc9d3baebaed5646f3a954e95f85745f9ff
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMedScopus

Authority records

Herdenberg, CarlBilling, OlaAbdullah, AhmadTuck, SimonHolmlund, CamillaHenriksson, RogerHedman, Håkan

Search in DiVA

By author/editor
Herdenberg, CarlBilling, OlaAbdullah, AhmadStrawbridge, Rona J.Tuck, SimonHolmlund, CamillaHenriksson, RogerHedman, Håkan
By organisation
OncologySurgeryUmeå Centre for Molecular Medicine (UCMM)
In the same journal
Communications Biology
Cell and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar
Total: 176 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 660 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf