Neuroretina specification in mouse embryos requires Six3-mediated suppression of Wnt8b in the anterior neural plate.

Retinal degeneration causes vision impairment and blindness in humans. If one day we are to harness the potential of stem cell-based cell replacement therapies to treat these conditions, it is imperative that we better understand normal retina development. Currently, the genes and mechanisms that regulate the specification of the neuroretina during vertebrate eye development remain unknown. Here, we identify sine oculis-related homeobox 3 (Six3) as a crucial player in this process in mice. In Six3 conditional-mutant mouse embryos, specification of the neuroretina was abrogated, but that of the retinal pigmented epithelium was normal. Conditional deletion of Six3 did not affect the initial development of the optic vesicle but did arrest subsequent neuroretina specification. Ectopic rostral expansion of Wnt8b expression was the major response to Six3 deletion and the leading cause for the specific lack of neuroretina, as ectopic Wnt8b expression in transgenic embryos was sufficient to suppress neuroretina specification. Using chromatin immunoprecipitation assays, we identified Six3-responsive elements in the Wnt8b locus and demonstrated that Six3 directly repressed Wnt8b expression in vivo. Our findings provide a molecular framework to the program leading to neuroretina differentiation and may be relevant for the development of novel strategies aimed at characterizing and eventually treating different abnormalities in eye formation.

Neural tube defects in Mexican-Americans living on the US-Mexico border: The effects of folic acid and dietary folate

Neural tube defects (NTDs) are malformations of the developing brain and spinal cord; the most common are anencephaly and spina bifida. Evidence from many populations suggests that 50% of NTDs can be prevented through daily consumption of folic acid. A recent study has reported that folic acid may not protect populations of Mexican descent. This finding has serious implications for women living along the US-Mexico border. Not only is risk high in these Mexican American women compared with other US women; they also differ markedly in supplemental folic acid and dietary folate consumption, and in NTD-related risks (e.g., obesity, diabetes). This case-control study investigated whether folic acid supplements and dietary folate reduces NTDs in Mexican Americans. Cases included liveborn, stillborn, electively and spontaneously aborted NTD-affected fetuses and infants occurring in the 14-county Texas-Mexico border. Controls were randomly selected from unaffected live births, frequency matched to cases by hospital and year. An in-person interview of 110 case and 113 control mothers solicited data on folic acid supplements, dietary folate, and other covariates. Consumption of folic acid-containing vitamins before conception was only 5% for both case and control women. Taking vitamins the trimester before conception had no apparent effect, after adjusting for covariates [odds ratio (OR) = 1.0, 95% confidence interval (CI) = 0.3–3.4]. Combining folate from vitamins and diet showed a 20% risk reduction for women consuming at least 400 μg of folate daily [OR = 0.8, 95% CI = 0.5–1.5]; however, this estimate is statistically indistinguishable from the null. Although consistent with an inherent ineffectiveness of supplemental folic acid, that so few women consumed multivitamins during the critical time severely limited the assessment of folic acid in this population. A reduced folate response in Mexican descent women may be due to a genetic heterogeneity for metabolizing folate. Alternatively, folate intakes may be insufficient to overcome other underlying risk factors. In conclusion, determining whether folic acid reduces NTD risk in Mexican American women requires further study in populations with higher folic acid exposures. Meanwhile, we should pursue all recommended prevention strategies to reduce risk, including motivating Mexican American women of childbearing age to take folic acid routinely. ^