Radical and lunatic fringes modulate notch ligands to support mammalian intestinal homeostasis

Preetish Kadur Lakshminarasimha Murthy; Tara Srinivasan; Matthew S Bochter; Rui Xi; Anastasia Kristine Varanko; Kuei-Ling Tung; Fatih Semerci; Keli Xu; Mirjana Maletic-Savatic; Susan E Cole; Xiling Shen

doi:10.7554/eLife.35710

Radical and lunatic fringes modulate notch ligands to support mammalian intestinal homeostasis

Elife. 2018 Apr 9:7:e35710. doi: 10.7554/eLife.35710.

Authors

Preetish Kadur Lakshminarasimha Murthy^#^{1

2}, Tara Srinivasan^#³, Matthew S Bochter⁴, Rui Xi¹, Anastasia Kristine Varanko³, Kuei-Ling Tung^{1

5}, Fatih Semerci⁶, Keli Xu⁷, Mirjana Maletic-Savatic⁶, Susan E Cole⁴, Xiling Shen^{1

3

8}

Affiliations

¹ Center for Genomics and Computational Biology, Department of Biomedical Engineering, Duke University, Durham, United States.
² Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, United States.
³ Mienig School of Biomedical Engineering, Cornell University, Ithaca, United States.
⁴ Department of Molecular Genetics, Ohio State University, Columbus, United States.
⁵ Department of Biological and Environmental Engineering, Cornell University, Ithaca, United States.
⁶ Department of Pediatrics, Baylor College of Medicine, Houston, United States.
⁷ Department of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, Jackson, United States.
⁸ School of Electrical and Computer Engineering, Cornell University, Ithaca, United States.

^# Contributed equally.

Abstract

Notch signalling maintains stem cell regeneration at the mouse intestinal crypt base and balances the absorptive and secretory lineages in the upper crypt and villus. Here we report the role of Fringe family of glycosyltransferases in modulating Notch activity in the two compartments. At the crypt base, RFNG is enriched in the Paneth cells and increases cell surface expression of DLL1 and DLL4. This promotes Notch activity in the neighbouring Lgr5+ stem cells assisting their self-renewal. Expressed by various secretory cells in the upper crypt and villus, LFNG promotes DLL surface expression and suppresses the secretory lineage . Hence, in the intestinal epithelium, Fringes are present in the ligand-presenting 'sender' secretory cells and promote Notch activity in the neighbouring 'receiver' cells. Fringes thereby provide for targeted modulation of Notch activity and thus the cell fate in the stem cell zone, or the upper crypt and villus.

Keywords: Fringe; Glycosylation; Intestinal Crypts; Lgr5+ Stem Cell; Notch Signalling; cell biology; developmental biology; mouse; stem cells.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adaptor Proteins, Signal Transducing
Animals
Calcium-Binding Proteins
Cell Differentiation
Cell Proliferation
Cells, Cultured
Glucosyltransferases
Glycosyltransferases
Homeostasis*
Intercellular Signaling Peptides and Proteins / genetics
Intercellular Signaling Peptides and Proteins / metabolism*
Intestines / cytology
Intestines / physiology*
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism*
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
Proteins / physiology
Receptors, G-Protein-Coupled / physiology
Receptors, Notch / genetics
Receptors, Notch / metabolism*
Signal Transduction
Stem Cells / cytology*
Stem Cells / metabolism

Substances

Adaptor Proteins, Signal Transducing
Calcium-Binding Proteins
DLL4 protein, mouse
Dlk1 protein, mouse
Intercellular Signaling Peptides and Proteins
Intracellular Signaling Peptides and Proteins
Lgr5 protein, mouse
Membrane Proteins
Proteins
Receptors, G-Protein-Coupled
Receptors, Notch
Glycosyltransferases
Glucosyltransferases
Mfng protein, mouse
Rfng protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding