Retinoic acid synthesis and autoregulation mediate zonal patterning of vestibular organs and inner ear morphogenesis.

Retinoic acid (RA), a vitamin A (retinol) derivative, has pleiotropic functions during embryonic development. The synthesis of RA requires two enzymatic reactions: oxidation of retinol into retinaldehyde by alcohol dehydrogenases (ADHs) or retinol dehydrogenases (RDHs); and oxidation of retinaldehyde into RA by aldehyde dehydrogenases family 1, subfamily A (ALDH1as), such as ALDH1a1, ALDH1a2 and ALDH1a3. Levels of RA in tissues are regulated by spatiotemporal expression patterns of genes encoding RA-synthesizing and -degrading enzymes, such as cytochrome P450 26 (Cyp26 genes). Here, we show that RDH10 is important for both sensory and non-sensory formation of the vestibule of the inner ear. Mice deficient in Rdh10 exhibit failure of utricle-saccule separation, otoconial formation and zonal patterning of vestibular sensory organs. These phenotypes are similar to those of Aldh1a3 knockouts, and the sensory phenotype is complementary to that of Cyp26b1 knockouts. Together, these results demonstrate that RDH10 and ALDH1a3 are the key RA-synthesis enzymes involved in vestibular development. Furthermore, we discovered that RA induces Cyp26b1 expression in the developing vestibular sensory organs, which generates the differential RA signaling required for zonal patterning.

Inhibitory effect of chitooligosaccharides on retinol metabolism and bioavailability in mice.

This study investigated the intervention effects of chitooligosaccharides (COS) on retinol metabolism and included comparisons of the retinol level, retinol binding protein 4 (RBP4) content, key genes, and protein expression between mice on a COS-enriched diet and a normal diet. The results showed that COS markedly decreased the retinol and RBP4 concentrations in the serum and liver. Furthermore, COS suppressed the mRNA and protein expression of RBP4, cellular retinol binding protein 1 (CRBP1), lecithin: retinol acyltransferase (LRAT) and cytochrome P45026A1 (CYP26A1). In addition, COS inhibited the mRNA expression of stimulated by retinoic acid 6 (STRA6). However, the protein expression of STRA6 was not significantly decreased. Thus, COS reduced the retinol concentration in the serum and disrupted the metabolism of retinol. The intervention mechanism of COS on retinol metabolism may be attributed to the modulation of RBP4, CRBP1, LRAT, STRA6, and CYP26A1 expression at the mRNA and protein levels. PRACTICAL APPLICATIONS: Chitooligosaccharides (COS), known to be the degradation products of chitosan, have been found to induce pinkeye in industrial workers who participate in the manufacturing of COS. Meanwhile, 5% population with COS dietary supplement also have similar phenomenon. The aim of this study is to explore the possible mechanism underlay of this potential risk. The results of this study showed that high exposure to COS during manufacture influences retinol metabolism and leads to a decrease in retinol content, ultimately causing pinkeye. These findings provide new evidence for understanding COS-induced retinol metabolism alteration and drawing attention toward the prevention of potential risk in high-exposure populations.

The Thalamus Regulates Retinoic Acid Signaling and Development of Parvalbumin Interneurons in Postnatal Mouse Prefrontal Cortex.

GABAergic inhibitory neurons in the prefrontal cortex (PFC) play crucial roles in higher cognitive functions. Despite the link between aberrant development of PFC interneurons and a number of psychiatric disorders, mechanisms underlying the development of these neurons are poorly understood. Here we show that the retinoic acid (RA)-degrading enzyme CYP26B1 (cytochrome P450 family 26, subfamily B, member 1) is transiently expressed in the mouse frontal cortex during postnatal development, and that medial ganglionic eminence (MGE)-derived interneurons, particularly in parvalbumin (PV)-expressing neurons, are the main cell type that has active RA signaling during this period. We found that frontal cortex-specific Cyp26b1 knock-out mice had an increased density of PV-expressing, but not somatostatin-expressing, interneurons in medial PFC, indicating a novel role of RA signaling in controlling PV neuron development. The initiation of Cyp26b1 expression in neonatal PFC coincides with the establishment of connections between the thalamus and the PFC. We found that these connections are required for the postnatal expression of Cyp26b1 in medial PFC. In addition to this region-specific role in postnatal PFC that regulates RA signaling and PV neuron development, the thalamocortical connectivity had an earlier role in controlling radial dispersion of MGE-derived interneurons throughout embryonic neocortex. In summary, our results suggest that the thalamus plays multiple, temporally separate roles in interneuron development in the PFC.

9-cis ß-Carotene Increased Cholesterol Efflux to HDL in Macrophages.

Cholesterol efflux from macrophages is a key process in reverse cholesterol transport and, therefore, might inhibit atherogenesis. 9-cis-ß-carotene (9-cis-ßc) is a precursor for 9-cis-retinoic-acid (9-cis-RA), which regulates macrophage cholesterol efflux. Our objective was to assess whether 9-cis-ßc increases macrophage cholesterol efflux and induces the expression of cholesterol transporters. Enrichment of a mouse diet with ßc from the alga Dunaliella led to ßc accumulation in peritoneal macrophages. 9-cis-ßc increased the mRNA levels of CYP26B1, an enzyme that regulates RA cellular levels, indicating the formation of RA from ßc in RAW264.7 macrophages. Furthermore, 9-cis-ßc, as well as all-trans-ßc, significantly increased cholesterol efflux to high-density lipoprotein (HDL) by 50% in RAW264.7 macrophages. Likewise, food fortification with 9-cis-ßc augmented cholesterol efflux from macrophages ex vivo. 9-cis-ßc increased both the mRNA and protein levels of ABCA1 and apolipoprotein E (APOE) and the mRNA level of ABCG1. Our study shows, for the first time, that 9-cis-ßc from the diet accumulates in peritoneal macrophages and increases cholesterol efflux to HDL. These effects might be ascribed to transcriptional induction of ABCA1, ABCG1, and APOE. These results highlight the beneficial effect of ßc in inhibition of atherosclerosis by improving cholesterol efflux from macrophages.