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Review
. 2023 Jun 22:17:1155758.
doi: 10.3389/fnins.2023.1155758. eCollection 2023.

Role of vitamin C and SVCT2 in neurogenesis

Katterine Salazar #  1   2 , Nery Jara #  3 , Eder Ramírez  1 , Isabelle de Lima  1 , Javiera Smith-Ghigliotto  1 , Valentina Muñoz  3 , Luciano Ferrada  2 , Francisco Nualart  1   2
Affiliations
Review

Role of vitamin C and SVCT2 in neurogenesis

Katterine Salazar et al. Front Neurosci. .

Abstract

Different studies have established the fundamental role of vitamin C in proliferation, differentiation, and neurogenesis in embryonic and adult brains, as well as in in vitro cell models. To fulfill these functions, the cells of the nervous system regulate the expression and sorting of sodium-dependent vitamin C transporter 2 (SVCT2), as well as the recycling of vitamin C between ascorbic acid (AA) and dehydroascorbic acid (DHA) via a bystander effect. SVCT2 is a transporter preferentially expressed in neurons and in neural precursor cells. In developmental stages, it is concentrated in the apical region of the radial glia, and in adult life, it is expressed preferentially in motor neurons of the cerebral cortex, starting on postnatal day 1. In neurogenic niches, SVCT2 is preferentially expressed in precursors with intermediate proliferation, where a scorbutic condition reduces neuronal differentiation. Vitamin C is a potent epigenetic regulator in stem cells; thus, it can induce the demethylation of DNA and histone H3K27m3 in the promoter region of genes involved in neurogenesis and differentiation, an effect mediated by Tet1 and Jmjd3 demethylases, respectively. In parallel, it has been shown that vitamin C induces the expression of stem cell-specific microRNA, including the Dlk1-Dio3 imprinting region and miR-143, which promotes stem cell self-renewal and suppresses de novo expression of the methyltransferase gene Dnmt3a. The epigenetic action of vitamin C has also been evaluated during gene reprogramming of human fibroblasts to induced pluripotent cells, where it has been shown that vitamin C substantially improves the efficiency and quality of reprogrammed cells. Thus, for a proper effect of vitamin C on neurogenesis and differentiation, its function as an enzymatic cofactor, modulator of gene expression and antioxidant is essential, as is proper recycling from DHA to AA by various supporting cells in the CNS.

Keywords: SVCT2; ascorbic acid; epigenetic reprogramming; neurogenesis; neuronal differentiation; pluripotency; radial glia cells; vitamin C.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Vitamin C homeostasis in the nervous system. Vitamin C enters the CSF through the choroid plexus. SVCT2 and GLUT1 are expressed basolaterally (green and yellow, respectively). GLUT12 (purple, apical) could be the apical polarized transporter for the transport of vitamin C within the CSF (Miyata et al., 2022). Once vitamin C is concentrated in brain tissue, it is incorporated into neurons using SVCT2. Intracellular oxidation generates DHA, a molecule that can leave neurons through GLUT3. DHA is incorporated into astrocytes to be reduced to AA and released back into the extracellular space. Most astrocytes do not express SVCT2; however, marginal glia have been shown to express it (Nualart et al., 2012).
FIGURE 2
FIGURE 2
Expression of SVCT2 during embryonic brain development and in early postnatal stages. SVCT2 has been detected in radial glia, with apical polarization (Silva-Alvarez et al., 2017). Its expression varies during development, increasing in radial glia at the peak of neurogenesis. SVCT2 is also expressed in vitro when radial glia form neurospheres with nestin + cells. If neurospheres are attached to the substrate, the cells have processes that are strongly stimulated by vitamin C (Espinoza et al., 2020). In postnatal stages, the expression of SVCT2 increases again in the cerebral cortex; later, the transporter is detected primarily in motor neurons. In this period, the beginning of the recycling of vitamin C between neurons and astrocytes is necessary once the astrocytes are differentiated. If vitamin C recycling is disrupted, blocking GLUT1 function in astrocytes, neurons lose their processes (Salazar et al., 2021). The recycling of vitamin C is essential for neuronal development and arborization.
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Grants and funding

This work was supported by VRID-UDEC grant number 01-2022000481INV (KS), CONICYT PIA grant number ECM-12, Fondecyt grant number 1221147 (FN) and Fondecyt grant number 11170959 (NJ).

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