Regulation of neural stem cell differentiation and brain development by MGAT5-mediated N-glycosylation

Andrew R Yale; Estelle Kim; Brenda Gutierrez; J Nicole Hanamoto; Nicole S Lav; Jamison L Nourse; Marc Salvatus; Robert F Hunt; Edwin S Monuki; Lisa A Flanagan

doi:10.1016/j.stemcr.2023.04.007

Regulation of neural stem cell differentiation and brain development by MGAT5-mediated N-glycosylation

Stem Cell Reports. 2023 Jun 13;18(6):1340-1354. doi: 10.1016/j.stemcr.2023.04.007. Epub 2023 May 11.

Authors

Affiliations

¹ Department of Anatomy & Neurobiology, University of California Irvine, Irvine, CA 92697, USA; Department of Neurology, University of California Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA 92697, USA.
² Department of Neurology, University of California Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA 92697, USA.
³ Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA 92697, USA.
⁴ Department of Anatomy & Neurobiology, University of California Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA 92697, USA.
⁵ Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA 92697, USA; Department of Pathology & Laboratory Medicine, University of California Irvine, Irvine, CA 92697, USA.
⁶ Department of Anatomy & Neurobiology, University of California Irvine, Irvine, CA 92697, USA; Department of Neurology, University of California Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA 92697, USA; Department of Biomedical Engineering, University of California Irvine, Irvine, CA 92697, USA. Electronic address: lisa.flanagan@uci.edu.

Abstract

Undifferentiated neural stem and progenitor cells (NSPCs) encounter extracellular signals that bind plasma membrane proteins and influence differentiation. Membrane proteins are regulated by N-linked glycosylation, making it possible that glycosylation plays a critical role in cell differentiation. We assessed enzymes that control N-glycosylation in NSPCs and found that loss of the enzyme responsible for generating β1,6-branched N-glycans, N-acetylglucosaminyltransferase V (MGAT5), led to specific changes in NSPC differentiation in vitro and in vivo. Mgat5 homozygous null NSPCs in culture formed more neurons and fewer astrocytes compared with wild-type controls. In the brain cerebral cortex, loss of MGAT5 caused accelerated neuronal differentiation. Rapid neuronal differentiation led to depletion of cells in the NSPC niche, resulting in a shift in cortical neuron layers in Mgat5 null mice. Glycosylation enzyme MGAT5 plays a critical and previously unrecognized role in cell differentiation and early brain development.

Keywords: MGAT5; N-glycan branching; astrocyte; brain; cerebral cortex; glycosylation; neural stem cell; neuron.

MeSH terms

Animals
Brain* / growth & development
Glycosylation
Membrane Proteins*
Mice
Mice, Knockout
Neurogenesis*

Substances

Membrane Proteins
alpha-1,6-mannosylglycoprotein beta 1,6-N-acetylglucosaminyltransferase