Low availability of choline in utero disrupts development and function of the retina

Abstract

Adequate supply of choline, an essential nutrient, is necessary to support proper brain development. Whether prenatal choline availability plays a role in development of the visual system is currently unknown. In this study, we addressed the role of in utero choline supply for the development and later function of the retina in a mouse model. We lowered choline availability in the maternal diet during pregnancy and assessed proliferative and differentiation properties of retinal progenitor cells (RPCs) in the developing prenatal retina, as well as visual function in adult offspring. We report that low choline availability during retinogenesis leads to persistent retinal cytoarchitectural defects, ranging from focal lesions with displacement of retinal neurons into subretinal space to severe hypocellularity and ultrastructural defects in photoreceptor organization. We further show that low choline availability impairs timely differentiation of retinal neuronal cells, such that the densities of early‐born retinal ganglion cells, amacrine and horizontal cells, as well as cone photoreceptor precursors, are reduced in low choline embryonic d 17.5 retinas. Maintenance of higher proportions of RPCs that fail to exit the cell cycle underlies aberrant neuronal differentiation in low choline embryos. Increased RPC cell cycle length, and associated reduction in neurofibromin 2/Merlin protein, an upstream regulator of the Hippo signaling pathway, at least in part, explain aberrant neurogenesis in low choline retinas. Furthermore, we find that animals exposed to low choline diet in utero exhibit a significant degree of intraindividual variation in vision, characterized by marked functional discrepancy between the 2 eyes in individual animals. Together, our findings demonstrate, for the first time, that choline availability plays an essential role in the regulation of temporal progression of retinogenesis and provide evidence for the importance of adequate supply of choline for proper development of the visual system.—Trujillo‐Gonzalez, I., Friday, W. B., Munson, C. A., Bachleda, A., Weiss, E. R., Alam, N. M., Sha, W., Zeisel, S. H., Surzenko, N. Low availability of choline in utero disrupts development and function of the retina. FASEB J. 33, 9194–9209 (2019). http://www.fasebj.org

Role of Choline in Ocular Diseases

“…The retina is derived from the neuroepithelium of the ventral diencephalon [ 65 ]. Choline also facilitates optimal retinal development [ 66 , 67 ]. Choline acetyltransferase-expressing retinal amacrine cells exist in the retinas of human and vertebral animals [ 68 ].…”

“…The choline acetyltransferase in the outer plexiform layer of the retina slowly reduces during larval development [ 69 ]. Choline plays a critical role in the regulation of the temporal progression of retinogenesis, and adequate choline supplementation is essential for optimal development of the visual system [ 67 ]. Choline deficiency leads to impairments in the differentiation of retinal neuronal cells, such as the densities of early born retinal ganglion cells, amacrine and horizontal cells, and cone photoreceptor precursors [ 67 ].…”

Choline: Exploring the Growing Science on Its Benefits for Moms and Babies

“…For example, piglets born to choline-deficient mothers had lower brain weight, volume, and less white and grey matter at 30 days of age as compared to control piglets [73,74,75]. A recent study reported that low choline during gestation also disrupted retinal development and visual function in mice [77]. Possible mechanisms by which maternal choline influences offspring neurodevelopment and cognitive function are related to (i) the use of choline for phospholipid membrane synthesis; (ii) facilitation of DHA uptake [21]; (iii) myelination of neurons during early development [13,78]; (iv) alterations in hippocampal acetylcholine metabolism [28,79]; (v) modulation of neurogenesis and neuronal differentiation [76,77]; and (vi) modifications on epigenetic marks that govern hippocampal angiogenesis and cellular proliferation [33,34].…”

“…A recent study reported that low choline during gestation also disrupted retinal development and visual function in mice [77]. Possible mechanisms by which maternal choline influences offspring neurodevelopment and cognitive function are related to (i) the use of choline for phospholipid membrane synthesis; (ii) facilitation of DHA uptake [21]; (iii) myelination of neurons during early development [13,78]; (iv) alterations in hippocampal acetylcholine metabolism [28,79]; (v) modulation of neurogenesis and neuronal differentiation [76,77]; and (vi) modifications on epigenetic marks that govern hippocampal angiogenesis and cellular proliferation [33,34]. All of these choline-induced outcomes ultimately influence cellular proliferation, differentiation, morphology, dendritic branching, neurogenesis, and potentiation of the offspring hippocampus [76,80,81,82].…”

Insufficient dietary choline aggravates disease severity in a mouse model of Citrobacter rodentium-induced colitis

“…Evidence suggests that, for a significant number of individuals, choline consumption is far below the adequate intake (9) . For example, only 7 % of women in developed countries and fewer in developing countries consistently achieve the daily recommended intake of choline (11) . Growing evidence highlights a critical role for choline in health and links inadequate choline intake to impaired liver and muscle function in humans and other animals (12) .…”