👤 Antolin Canto

Steroid hormones, particularly estrogens, modulate neuronal survival in the central nervous system and the retina; however, their specific cell-type-specific roles in the human retina remain incompletely characterized. We analyzed the single-cell RNA sequencing dataset E-MTAB-7316 to profile genes from the KEGG steroid hormone biosynthesis and oestrogen signalling pathways. Functional relevance of local oestrogen synthesis was tested in mouse retinal explants treated with the aromatase inhibitor letrozole (20 μM). Over 50% of steroid hormone metabolism genes were expressed in retinal cells, with cell-type specificity. COMT, HSD17B12, and HSD11B1L were broadly distributed, while LRTOMT, HSD17B7, and SRD5A1 were enriched in rod photoreceptors. Among oestrogen signalling genes, 114/139 were detected, with HSP90AA1 as the most abundant. When oestrogen synthesis was blocked with letrozole, retinal explants showed increased cell death, particularly in the outer nuclear layer, without inducing macrogliosis but with significant microglial activation (IBA1+). Our data indicate that the human retina expresses multiple components of steroid hormone metabolism and oestrogen signalling. The results are consistent with a potential role of locally synthesized oestrogens in photoreceptor maintenance and immune regulation, which may warrant further investigation as a possible avenue for retinal protection. Show less

Li-Fraumeni syndrome (LFS) is a hereditary disorder that predisposes patients to several types of cancer and is associated with TP53 germline mutations. Turner syndrome (TS) is one of the most common aneuploidies in women. Patients with TS have a higher risk of developing cancer, although multiple malignant tumors are extremely rare. Herein, we describe a patient with a 45,X/46,XX karyotype with no classic phenotype of TS. She presented with a clinical diagnosis of Li-Fraumeni-like syndrome (LFL), showing papillary thyroid carcinoma and fibrosarcoma of the left flank, and had no TP53 germline mutations. Genome-wide analysis of copy number variations (CNVs) was assessed in DNA from peripheral blood cells and saliva. A total of 109 rare CNVs in the blood cells, including mosaic loss of the X chromosome (76% of cells), were identified. In saliva, three rare CNVs were detected, all of them were also detected in the blood cells: loss of 8q24.11 (EXT1), gain of 16q24.3 (PRDM7 and GAS8), and the mosaic loss of the X chromosome (50% of cells). Results of conventional G-banding confirmed the 45,X/46,XX karyotype. Surprisingly, the patient presented with an apparently normal phenotype. The PRDM and GAS8 genes are potential candidates to be associated with the risk of developing cancer in this LFL/TS patient. Show less

The nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase SIRT1 is a major metabolic regulator activated by energy stresses such as fasting or calorie restriction. SIRT1 activation during fasting not only relies on the increase in the NAD(+)/NADH ratio caused by energy deprivation but also involves an upregulation of SIRT1 mRNA and protein levels in various metabolic tissues. We demonstrate that SIRT1 expression is controlled systemically by the activation of the cyclic AMP response-element-binding protein upon low nutrient availability. Conversely, in the absence of energetic stress, the carbohydrate response-element-binding protein represses the expression of SIRT1. Altogether, these results demonstrate that SIRT1 expression is tightly controlled at the transcriptional level by nutrient availability and further underscore that SIRT1 is a crucial metabolic checkpoint connecting the energetic status with transcriptional programmes. Show less