Vitamin B12 Regulates Glial Migration and Synapse Formation through Isoform-Specific Control of PTP-3/LAR PRTP Expression

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SUMMARY

Vitamin B12 is known to play critical roles during the development and aging of the brain, and vitamin B12 deficiency has been linked to neurodevelopmental and degenerative disorders. However, the underlying molecular mechanisms of how vitamin B12 affects the development and maintenance of the nervous system are still unclear. Here, we report that vitamin B12 can regulate glial migration and synapse formation through control of isoform-specific expression of PTP-3/LAR PRTP (leukocyte-common antigen-related receptor-type tyrosine-protein phosphatase). We found the uptake of diet-supplied vitamin B12 in the intestine to be critical for the expression of a long isoform of PTP-3 (PTP-3A) in neuronal and glial cells. The expression of PTP-3A cell autonomously regulates glial migration and synapse formation through interaction with an extracellular matrix protein NID-1/nidogen 1. Together, our findings demonstrate that isoform-specific regulation of PTP-3/ LAR PRTP expression is a key molecular mechanism that mediates vitamin-B12-dependent neuronal and glial development.

In Brief

Zhang et al. describe glial migration and synapse formation defects stemming from vitamin B12 deficiency. Their study identifies a cell-autonomous mechanism regulating glial migration, where vitamin B12 regulates expression of the cell adhesion molecule PTP-3/LAR PRTP in an isoform-specific manner.

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Most cited references 57

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Mutant sensory cilia in the nematode Caenorhabditis elegans.

L Perkins, E M Hedgecock, J N Thomson … (1986)

Eight classes of chemosensory neurons in C. elegans fill with fluorescein when living animals are placed in a dye solution. Fluorescein enters the neurons through their exposed sensory cilia. Mutations in 14 genes prevent dye uptake and disrupt chemosensory behaviors. Each of these genes affects the ultrastructure of the chemosensory cilia or their accessory cells. In each case, the cilia are shorter or less exposed than normal, suggesting that dye contact is the principal factor under selection. Ten genes affect many or all of the sensory cilia in the head. The daf-19 (m86) mutation eliminates all cilia, leaving only occasional centrioles in the dendrites. The cilia in che-13 (e1805), osm-1 (p808), osm-5 (p813), and osm-6 (p811) mutants have normal transition zones and severely shortened axonemes. Doublet-microtubules, attached to the membrane by Y links, assemble ectopically proximal to the cilia in these mutants. The amphid cilia in che-11 (e1810) are irregular in diameter and contain dark ground material in the middle of the axonemes. Certain mechanocilia are also affected. The amphid cilia in che-10 (e1809) apparently degenerate, leaving dendrites with bulb-shaped endings filled with dark ground material. The mechanocilia lack striated rootlets. Cilia defects have also been found in che-2, che-3, and daf-10 mutants. The osm-3 (p802) mutation specifically eliminates the distal segment of the amphid cilia. Mutations in three genes affect sensillar support cells. The che-12 (e1812) mutation eliminates matrix material normally secreted by the amphid sheath cell. The che-14 (e1960) mutation disrupts the joining of the amphid sheath and socket cells to form the receptor channel. A similar defect has been observed in daf-6 mutants. Four additional genes affect specific classes of ciliated sensory neurons. The mec-1 and mec-8 (e398) mutations disrupt the fasciculation of the amphid cilia. The cat-6 (e1861) mutation disrupts the tubular bodies of the CEP mechanocilia. A cryophilic thermotaxis mutant, ttx-1 (p767), lacks fingers on the AFD dendrite, suggesting this neuron is thermosensory.

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Vitamin B12, folic acid, and the nervous system.

Edward Reynolds (2006)

There are many reasons for reviewing the neurology of vitamin-B12 and folic-acid deficiencies together, including the intimate relation between the metabolism of the two vitamins, their morphologically indistinguishable megaloblastic anaemias, and their overlapping neuropsychiatric syndromes and neuropathology, including their related inborn errors of metabolism. Folates and vitamin B12 have fundamental roles in CNS function at all ages, especially the methionine-synthase mediated conversion of homocysteine to methionine, which is essential for nucleotide synthesis and genomic and non-genomic methylation. Folic acid and vitamin B12 may have roles in the prevention of disorders of CNS development, mood disorders, and dementias, including Alzheimer's disease and vascular dementia in elderly people.

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Author and article information

Journal

Journal ID (nlm-journal-id): 101573691

Journal ID (pubmed-jr-id): 39703

Journal ID (nlm-ta): Cell Rep

Journal ID (iso-abbrev): Cell Rep

Title: Cell reports

ISSN (Electronic): 2211-1247

Publication date Nihms-submitted: 17 May 2020

Publication date (Print): 24 March 2020

Publication date PMC-release: 09 June 2020

Volume: 30

Issue: 12

Pages: 3981-3988.e3

Affiliations

[1 ]Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA

[2 ]Department of Molecular Biosciences, The University of Kansas, Lawrence, KS 66045, USA

[3 ]Department of Neurobiology, Regeneration Next Initiative, and Duke Institute for Brain Sciences, Duke University Medical Center, Durham, NC 27710, USA

[4 ]Lead Contact

Author notes

AUTHOR CONTRIBUTIONS

A.Z. and D.Y. devised the whole project. A.Z. characterized mrp-5, ptp-3, and nid-1 phenotypes and performed all molecular, genetic, and imaging experiments. B.D.A. provided reagents and shared unpublished results. A.Z. and D.Y. wrote the manuscript with input from all authors.

[* ]Correspondence: dong.yan@ 123456duke.edu

Article

Manuscript ID: NIHMS1593798

DOI: 10.1016/j.celrep.2020.02.113

PMC ID: 7281833

PubMed ID: 32209461

SO-VID: 3f774e2d-c0fd-4c8c-8ce1-ef96b54c9c15

License:

This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).

Vitamin B12 Regulates Glial Migration and Synapse Formation through Isoform-Specific Control of PTP-3/LAR PRTP Expression

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Most cited references 57

Mutant sensory cilia in the nematode Caenorhabditis elegans.

Gene regulation by riboswitches.

Vitamin B12, folic acid, and the nervous system.

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