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In mammalian testes, undifferentiated spermatogonia (A undiff ) undergo differentiation in response to retinoic acid (RA), while their progenitor states are partially maintained by fibroblast growth factors (FGFs). Sertoli valve (SV) is a region located at the terminal end of seminiferous tubule (ST) adjacent to the rete testis (RT), where the high density of A undiff is constitutively maintained with the absence of active spermatogenesis. However, the molecular and cellular characteristics of SV epithelia still remain unclear. In this study, we first identified the region-specific AKT phosphorylation in the SV Sertoli cells and demonstrated non-cell autonomous specialization of Sertoli cells in the SV region by performing a Sertoli cell ablation/replacement experiment. The expression of Fgf9 was detected in the RT epithelia, while the exogenous administration of FGF9 caused ectopic AKT phosphorylation in the Sertoli cells of convoluted ST. Furthermore, we revealed the SV region-specific expression of Cyp26a1 , which encodes an RA-degrading enzyme, and demonstrated that the increased RA levels in the SV region disrupt its pool of A undiff by inducing their differentiation. Taken together, RT-derived FGFs and low levels of RA signaling contribute to the non-cell-autonomous regionalization of the SV epithelia and its local maintenance of A undiff in the SV region.

Human height is a representative phenotype to elucidate genetic architecture. However, the majority of large studies have been performed in European population. To investigate the rare and low-frequency variants associated with height, we construct a reference panel ( N  = 3,541) for genotype imputation by integrating the whole-genome sequence data from 1,037 Japanese with that of the 1000 Genomes Project, and perform a genome-wide association study in 191,787 Japanese. We report 573 height-associated variants, including 22 rare and 42 low-frequency variants. These 64 variants explain 1.7% of the phenotypic variance. Furthermore, a gene-based analysis identifies two genes with multiple height-increasing rare and low-frequency nonsynonymous variants ( SLC27A3 and CYP26B1 ; P SKAT-O  < 2.5 × 10 −6 ). Our analysis shows a general tendency of the effect sizes of rare variants towards increasing height, which is contrary to findings among Europeans, suggesting that height-associated rare variants are under different selection pressure in Japanese and European populations. Thousands of genetic loci are known to associate with human height, but these are mainly based on studies in European ancestry populations. Here, Akiyama et al. construct a genotype reference panel for the Japanese population followed by GWAS and report 573 height associated variants in 191,787 Japanese.

Cholesterol efflux from macrophages is a key process in reverse cholesterol transport and, therefore, might inhibit atherogenesis. 9-cis-β-carotene (9-cis-βc) is a precursor for 9-cis-retinoic-acid (9-cis-RA), which regulates macrophage cholesterol efflux. Our objective was to assess whether 9-cis-βc increases macrophage cholesterol efflux and induces the expression of cholesterol transporters. Enrichment of a mouse diet with βc from the alga Dunaliella led to βc accumulation in peritoneal macrophages. 9-cis-βc increased the mRNA levels of CYP26B1, an enzyme that regulates RA cellular levels, indicating the formation of RA from βc in RAW264.7 macrophages. Furthermore, 9-cis-βc, as well as all-trans-βc, significantly increased cholesterol efflux to high-density lipoprotein (HDL) by 50% in RAW264.7 macrophages. Likewise, food fortification with 9-cis-βc augmented cholesterol efflux from macrophages ex vivo. 9-cis-βc 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-βc 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 βc in inhibition of atherosclerosis by improving cholesterol efflux from macrophages.

Cholestasis is defined as a reduction of bile secretion caused by a dysfunction of bile formation. Insufficient bile secretion into the intestine undermines the formation of micelles, which may result in the reduced absorption of lipids and fat-soluble vitamins. Here, we investigated the retinol homeostasis and the alterations of retinol metabolism-related genes, including β-carotene 15,15′ monooxygenase (BCMO), lecithin:retinol acyltransferase (LRAT), aldehyde dehydrogenase (ALDH), cytochrome P450 26A1 (CYP26A1), and retinoic acid receptors (RAR) β, in a α-naphthyl isothiocyanate (ANIT)-induced cholestasis rat model. Moreover, we examined the expression of the farnesoid X receptor (FXR) target genes. Our results showed that plasma retinol levels were decreased in ANIT rats compared to control rats. On the contrary, hepatic retinol levels were not different between the two groups. The expression of FXR target genes in the liver and intestine of cholestasis model rats was repressed. The BCMO expression was decreased in the liver and increased in the intestine of ANIT rats compared to control rats. Finally, the hepatic expression of LRAT, RARβ, and ALDH1A1 in cholestatic rats was decreased compared to the control rats, while the CYP26A1 expression of the liver was not altered. The increased expression of intestinal BCMO in cholestasis model rats might compensate for decreased circulatory retinol levels. The BCMO expression might be regulated in a tissue-specific manner to maintain the homeostasis of retinol.

Each vestibular sensory epithelium in the inner ear is divided morphologically and physiologically into two zones, called the striola and extrastriola in otolith organ maculae, and the central and peripheral zones in semicircular canal cristae. We found that formation of striolar/central zones during embryogenesis requires Cytochrome P450 26b1 (Cyp26b1)-mediated degradation of retinoic acid (RA). In Cyp26b1 conditional knockout mice, formation of striolar/central zones is compromised, such that they resemble extrastriolar/peripheral zones in multiple features. Mutants have deficient vestibular evoked potential (VsEP) responses to jerk stimuli, head tremor and deficits in balance beam tests that are consistent with abnormal vestibular input, but normal vestibulo-ocular reflexes and apparently normal motor performance during swimming. Thus, degradation of RA during embryogenesis is required for formation of highly specialized regions of the vestibular sensory epithelia with specific functions in detecting head motions. The coding of sensory inputs at the level of vestibular sensory organs is not well understood. In this study, the authors demonstrate that the formation of striolar/central zones during embryogenesis requires Cytochrome P450 26b1 (Cyp26b1)-mediated degradation of retinoic acid and show that Cyp26b1 cKO mice have abnormal vestibular evoked potentials and balance beam performance, but normal vestibular-ocular reflexes.

Regenerating limbs retain their proximodistal (PD) positional identity following amputation. This positional identity is genetically encoded by PD patterning genes that instruct blastema cells to regenerate the appropriate PD limb segment. Retinoic acid (RA) is known to specify proximal limb identity, but how RA signaling levels are established in the blastema is unknown. Here, we show that RA breakdown via CYP26B1 is essential for determining RA signaling levels within blastemas. CYP26B1 inhibition molecularly reprograms distal blastemas into a more proximal identity, phenocopying the effects of administering excess RA. We identify Shox as an RA-responsive gene that is differentially expressed between proximally and distally amputated limbs. Ablation of Shox results in shortened limbs with proximal skeletal elements that fail to initiate endochondral ossification. These results suggest that PD positional identity is determined by RA degradation and RA-responsive genes that regulate PD skeletal element formation during limb regeneration. How axolotl salamanders know what portion of the limb to regenerate remains a mystery. In this article, the authors show that precise retinoic acid degradation is critical for instructing regeneration of the appropriate limb segment.

Chronic alcohol consumption leads to a spectrum of liver disease that is associated with significant global mortality and morbidity. Alcohol is known to deplete hepatic vitamin A content, which has been linked to the pathogenesis of alcoholic liver disease. It has been suggested that induction of Cytochrome P450 2E1 (CYP2E1) contributes to alcohol-induced hepatic vitamin A depletion, but the possible contributions of other retinoid-catabolizing CYPs have not been well studied. The main objective of this study was to better understand alcohol-induced hepatic vitamin A depletion and test the hypothesis that alcohol-induced depletion of hepatic vitamin A is due to CYP-mediated oxidative catabolism. This hypothesis was tested in a mouse model of chronic alcohol consumption, including wild type and Cyp2e1 -/- mice. Our results show that chronic alcohol consumption is associated with decreased levels of hepatic retinol, retinyl esters, and retinoic acid. Moreover, the depletion of hepatic retinoid is associated with the induction of multiple retinoid catabolizing CYPs, including CYP26A1, and CYP26B1 in alcohol fed wild type mice. In Cyp2e1 -/- mice, alcohol-induced retinol decline is blunted but retinyl esters undergo a change in their acyl composition and decline upon alcohol exposure like WT mice. In conclusion, the alcohol induced decline in hepatic vitamin A content is associated with increased expression of multiple retinoid-catabolizing CYPs, including the retinoic acid specific hydroxylases CYP26A1 and CYP26B1.

Oculo-auriculo-vertebral spectrum (OAVS) is a developmental disorder characterized by hemifacial microsomia associated with ear, eyes and vertebrae malformations showing highly variable expressivity. Recently, MYT1, encoding the myelin transcription factor 1, was reported as the first gene involved in OAVS, within the retinoic acid (RA) pathway. Fifty-seven OAVS patients originating from Brazil were screened for MYT1 variants. A novel de novo missense variant affecting function, c.323C>T (p.(Ser108Leu)), was identified in MYT1, in a patient presenting with a severe form of OAVS. Functional studies showed that MYT1 overexpression downregulated all RA receptors genes (RARA, RARB, RARG), involved in RA-mediated transcription, whereas no effect was observed on CYP26A1 expression, the major enzyme involved in RA degradation, Moreover, MYT1 variants impacted significantly the expression of these genes, further supporting their pathogenicity. In conclusion, a third variant affecting function in MYT1 was identified as a cause of OAVS. Furthermore, we confirmed MYT1 connection to RA signaling pathway.

The accumulation of prostaglandin E2 (PGE 2 ) during chronic inflammation has been implicated in the progression of several cancers. Cyclooxygenase is the key synthesizing enzyme of PGE 2 , although the degradation enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) has received considerable attention recently. We investigated the molecular mechanisms of pancreatic ductal adenocarcinoma (PDAC) progression via 15-PGDH downregulation. Here, we found that 15-PGDH expression was inversely correlated with ALDH1, an important cancer stem cell-associated marker indicative of poor prognosis in humans. Moreover, we demonstrated that pharmacological inhibition of 15-PGDH enhanced CYP26A1 expression, leading to depletion of all- trans retinoic acid (ATRA) and expansion of the ALDH1-positive subset in both human PDAC cells and tumor cells of Kras LSL -G12D /+ ; Ptf1a Cre/+ (KC) mice. Furthermore, genetic deletion of 15-Pgdh in KC mice showed PGE 2 accumulation and ATRA depletion in the pancreas, resulting in PDAC with high levels of Aldh1 and Ki-67. Finally, ATRA replacement suppressed 15-PGDH inhibition-induced tumor progression in KC mice, and ATRA treatment attenuated Aldh1 activity in tumor cells isolated from the pancreas of 15-Pgdh −/− KC mice. These findings provide evidence that 15-PGDH inhibition enhances KRAS -driven tumor progression via ATRA depletion in the pancreas. Therefore, ATRA replacement could be a potential strategy for PDAC treatment.

The Chinese soft-shelled turtle ( Pelodiscus sinensis ) is an important aquaculture animal in China and exhibits growth dimorphism. Single-male cultures are often selected for higher economic efficiency. However, the mechanism of sex differentiation in P. sinensis is not well-known. In this study, a comparative transcriptome analysis of male (ZZ)- and 17β-oestradiol (E2)-induced pseudo-female (ZZ + E2)-stage embryonic gonads of P. sinensis was performed. A total of 420 differentially expressed genes (DEGs), which included 271 upregulated genes and 149 downregulated genes, were identified. These DEGs were mainly involved in several sex-related pathways, such as “ovarian steroidogenesis”, “steroid hormone biosynthesis”, “PPAR signalling pathway”, and “metabolism of xenobiotics by cytochrome P450”. In addition, 50 known and novel candidate genes involved in sex differentiation, such as the male-biased genes AMH , DMRT1 , TBX1 , and CYP26A1 and the female-biased genes CYP1A1 , RASD1 , and SOX17 , were investigated and identified. For further verification, the full-length cDNAs of SOX17 and CYP26A1 were obtained. SOX17 contains a 1218-bp ORF and encodes 405 amino acids containing an HMG functional domain unique to the Sox superfamily. CYP26A1 contains a 1485-bp ORF and encodes 494 amino acids. Different expression levels of SOX17 and CYP26A1 could be detected in all the tested tissues of males and females. Notably, the expression of CYP26A1 was markedly greater in the gonads of male embryos ( P  < 0.05) than in those of female embryos, whereas the expression of SOX17 showed the opposite trend ( P  < 0.05). Taken together, the RNA-seq and qRT‒PCR results suggested potential roles for SOX17 and CYP26A1 in promoting female and male gonadal development, respectively, in P. sinensis . Our results provide new evidence for the mechanism of sex differentiation in P. sinensis .