Maternal dietary intake of choline in mice regulates development of the cerebral cortex in the offspring

Maternal diets low in choline, an essential nutrient, increase the risk of neural tube defects and lead to low performance on cognitive tests in children. However, the consequences of maternal dietary choline deficiency for the development and structural organization of the cerebral cortex remain unknown. In this study, we fed mouse dams either control (CT) or low-choline (LC) diets and investigated the effects of choline on cortical development in the offspring. As a result of a low choline supply between embryonic day (E)11 and E17 of gestation, the number of 2 types of cortical neural progenitor cells (NPCs)-radial glial cells and intermediate progenitor cells-was reduced in fetal brains (P < 0.01). Furthermore, the number of upper layer cortical neurons was decreased in the offspring of dams fed an LC diet at both E17 (P < 0.001) and 4 mo of age (P < 0.001). These effects of LC maternal diet were mediated by a decrease in epidermal growth factor receptor (EGFR) signaling in NPCs related to the disruption of EGFR posttranscriptional regulation. Our findings describe a novel mechanism whereby low maternal dietary intake of choline alters brain development

MicroRNA-129-5p is regulated by choline availability and controls EGF receptor synthesis and neurogenesis in the cerebral cortex

Choline availability modulates neurogenesis and cerebral cortex development through the regulation of neural progenitor cell (NPC) proliferative and differentiation capacity. In this study, we demonstrated that cortical NPC self-renewal is controlled by choline via the expression of a microRNA (miR-129-5p), whose role in the developing brain has not been examined, and which, in turn, inhibits synthesis of the epidermal growth factor receptor (EGFR) protein. Specifically, we found that low choline (LC) availability led to the upregulation of miR-129-5p expression in cortical NPCs in vitro and in vivo, causing the downregulation of EGFR and thereby disrupting NPC self-renewal and cortical neurogenesis. Furthermore, in response to LC availability, methylation potential (the S-adenosylmethionine:S-adenosylhomocysteine ratio) in the developing brain was reduced. Restoring methylation potential in LC cortical NPCs led to the re-establishment of normal miR-129-5p expression. We concluded that inhibiting miR-129-5p function and restoring EGFR protein levels in vivo is sufficient to reverse LC-induced defects in cortical NPC self-renewal. For the first time, to our knowledge, we have identified the molecular links that explain how a change in the availability of the diet metabolite choline impacts the essential cellular processes underlying brain development

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

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

DNA Methylomes Reveal Biological Networks Involved in Human Eye Development, Functions and Associated Disorders

Abstract This work provides a comprehensive CpG methylation landscape of the different layers of the human eye that unveils the gene networks associated with their biological functions and how these are disrupted in common visual disorders. Herein, we firstly determined the role of CpG methylation in the regulation of ocular tissue-specification and described hypermethylation of retinal transcription factors (i.e., PAX6, RAX, SIX6) in a tissue-dependent manner. Second, we have characterized the DNA methylome of visual disorders linked to internal and external environmental factors. Main conclusions allow certifying that crucial pathways related to Wnt-MAPK signaling pathways or neuroinflammation are epigenetically controlled in the fibrotic disorders involved in retinal detachment, but results also reinforced the contribution of neurovascularization (ETS1, HES5, PRDM16) in diabetic retinopathy. Finally, we had studied the methylome in the most frequent intraocular tumors in adults and children (uveal melanoma and retinoblastoma, respectively). We observed that hypermethylation of tumor suppressor genes is a frequent event in ocular tumors, but also unmethylation is associated with tumorogenesis. Interestingly, unmethylation of the proto-oncogen RAB31 was a predictor of metastasis risk in uveal melanoma. Loss of methylation of the oncogenic mir-17-92 cluster was detected in primary tissues but also in blood from patients