👤 Johannes von Lintig

Vitamin A is an essential nutrient crucial to ensuring proper mammalian embryonic development. β-Carotene is the most prevalent form of vitamin A in food that, when transferred in its intact form from mother to the developing tissues, can serve as an in situ source of retinoic acid, the active form of vitamin A. We have previously provided evidence that the maternal-fetal transfer of β-carotene across the placenta is mediated by lipoproteins and that β-carotene itself regulates placenta lipoprotein biogenesis by means of its derivatives β-apo-10'-carotenoids and retinoic acid. These metabolites exert antagonistic transcriptional activity on placental microsomal triglyceride transfer protein (MTP) and apolipoprotein B (APOB), two key players of lipoprotein biosynthesis. Here, we analyzed the time-dependency of this regulation over the course of 24 h upon a single maternal administration of β-carotene. We also tested the hypothesis that the transcriptional repressor intestine-specific homeobox (ISX) plays a role in the regulation of Mttp in placenta. We observed that ISX is expressed in placenta of mouse dams and is regulated by β-carotene availability. Furthermore, we demonstrated that the absence of Isx disrupts the β-carotene-mediated regulation of placental MTP. We also showed that this mechanism is organ-specific, as it was not observed in enterocytes of the intestine, a major place of Isx expression. Therefore, we identified ISX as a "master" regulator of a placental β-carotene-dependent transcriptional regulatory cascade that fine-tunes the flux of provitamin A carotenoid towards the developing fetus. Show less

The retinoic acid molecule, a vitamin A derivative, is of key importance for eye and photoreceptor development in vertebrates. Several studies have provided evidence that the ventral part of the retina is particularly susceptible to impairment in retinoid signalling during the period of its development. In zebrafish, targeted gene knockdown of beta,beta-carotene-15,15'-oxygenase (bcox), the key enzyme for vitamin A formation, provokes a loss of retinoid signalling during early eye development that results in microphthalmia at larval stages. Using this model, we analysed the consequences of this for the retinal morphology of the fish larvae in structural details. Our analyses revealed that rods and cones do not express photoreceptor specific proteins (rhodopsin, peanut agglutinin, zpr1) in the peripheral retina. The photoreceptors in the central retina showed shortened outer segments, and electron dense debris in their intermembranal space. The number of phagosomes was increased, and cell death was frequently observed in the outer nuclear layer. Furthermore, the number of Muller cells was significantly reduced in the inner nuclear layer. Thus, we found that the lack of retinoid signalling strongly effects photoreceptor development in the ventral and dorsal retina. In addition, shortened outer segments and cell death of the remaining photoreceptors in the central retina indicate that there is an ongoing need for retinoid signalling for photoreceptor integrity and survival at later developmental stages. Show less