Centrosome dysfunction associated with somatic expression of the synaptonemal complex protein TEX12

The synaptonemal complex (SC) is a supramolecular protein scaffold that mediates chromosome synapsis and facilitates crossing over during meiosis. In mammals, SC proteins are generally assumed to have no other function. Here, we show that SC protein TEX12 also localises to centrosomes during meiosis independently of chromosome synapsis. In somatic cells, ectopically expressed TEX12 similarly localises to centrosomes, where it is associated with centrosome amplification, a pathology correlated with cancer development. Indeed, TEX12 is identified as a cancer-testis antigen and proliferation of some cancer cells is TEX12-dependent. Moreover, somatic expression of TEX12 is aberrantly activated via retinoic acid signalling, which is commonly disregulated in cancer. Structure-function analysis reveals that phosphorylation of TEX12 on tyrosine 48 is important for centrosome amplification but not for recruitment of TEX12 to centrosomes. We conclude that TEX12 normally localises to meiotic centrosomes, but its misexpression in somatic cells can contribute to pathological amplification and dysfunction of centrosomes in cancers.

Maternal iron deficiency perturbs embryonic cardiovascular development in mice

Congenital heart disease (CHD) is the most common class of human birth defects, with a prevalence of 0.9% of births. However, two-thirds of cases have an unknown cause, and many of these are thought to be caused by in utero exposure to environmental teratogens. Here we identify a potential teratogen causing CHD in mice: maternal iron deficiency (ID). We show that maternal ID in mice causes severe cardiovascular defects in the offspring. These defects likely arise from increased retinoic acid signalling in ID embryos. The defects can be prevented by iron administration in early pregnancy. It has also been proposed that teratogen exposure may potentiate the effects of genetic predisposition to CHD through gene–environment interaction. Here we show that maternal ID increases the severity of heart and craniofacial defects in a mouse model of Down syndrome. It will be important to understand if the effects of maternal ID seen here in mice may have clinical implications for women.

Epilepsy-Associated UBE3A Deficiency Downregulates Retinoic Acid Signalling Pathway

Ubiquitin-protein ligase E3A (UBE3A) has dual functions as a E3 ubiquitin-protein ligase and coactivator of nuclear hormone receptors. Mutations or deletions of the maternally inherited UBE3A gene cause Angelman syndrome. Here, we performed transcriptome profiling in the hippocampus of Ube3am+/p+ and Ube3am–/p+ mice, and determined that the expression of the retinoic acid (RA) signalling pathway was downregulated in Ube3a-deficient mice compared to WT mice. Furthermore, we demonstrated that UBE3A directly interacts with RARα and may function as a coactivator of the nuclear receptor RARα to participate in the regulation of gene expression. Loss of UBE3A expression caused the downregulation of the expression of RA-related genes, including Erbb4, Dpysl3, Calb1, Pten, and Arhgap5 in Ube3am–/p+ mice brain tissues. This work revealed a new role for UBE3A in regulating retinoic acid (RA) signalling downstream genes and hopefully to shed light on the potential drug target of AS.

Mammalian adipogenesis regulators (Aregs) exhibit robust non- and anti-adipogenic properties that arise with age and involve retinoic acid signalling

Adipose stem and precursor cells (ASPCs) give rise to adipocytes and determine the composition and plasticity of adipose tissue. Recently, several studies have demonstrated that ASPCs partition into at least three distinct cell subpopulations: Dpp4+ stem-like cells, Aoc3+ pre-adipocyte-like cells, and the enigmatic CD142+ cells. A great challenge now is to functionally characterize these distinct ASPC populations. Here, we focus on CD142+ ASPCs since discrepant properties have been assigned to this subpopulation, from adipogenic to non- and even anti-adipogenic. To address these inconsistencies, we comprehensively characterized mammalian subcutaneous CD142+ ASPCs across various sampling conditions. Our findings demonstrate that CD142+ ASPCs exhibit high molecular and phenotypic robustness, firmly supporting their non- and anti-adipogenic properties. However, these properties emerge in an age-dependent manner, revealing surprising temporal CD142+ ASPC behavioural alterations. Finally, using multi-omic and functional assays, we show that the inhibitory nature of these adipogenesis-regulatory CD142+ ASPCs (Aregs) is driven by specifically expressed secretory factors that cooperate with the retinoic acid signalling pathway to transform the adipogenic state of CD142− ASPCs into a non-adipogenic, Areg-like one.

An improved de novo assembling and polishing of Solea senegalensis transcriptome shed light on retinoic acid signalling in larvae

Senegalese sole is an economically important flatfish species in aquaculture and an attractive model to decipher the molecular mechanisms governing the severe transformations occurring during metamorphosis, where retinoic acid seems to play a key role in tissue remodeling. In this study, a robust sole transcriptome was envisaged by reducing the number of assembled libraries (27 out of 111 available), fine-tuning a new automated and reproducible set of workflows for de novo assembling based on several assemblers, and removing low confidence transcripts after mapping onto a sole female genome draft. From a total of 96 resulting assemblies, two “raw” transcriptomes, one containing only Illumina reads and another with Illumina and GS-FLX reads, were selected to provide SOLSEv5.0, the most informative transcriptome with low redundancy and devoid of most single-exon transcripts. It included both Illumina and GS-FLX reads and consisted of 51,348 transcripts of which 22,684 code for 17,429 different proteins described in databases, where 9527 were predicted as complete proteins. SOLSEv5.0 was used as reference for the study of retinoic acid (RA) signalling in sole larvae using drug treatments (DEAB, a RA synthesis blocker, and TTNPB, a RA-receptor agonist) for 24 and 48 h. Differential expression and functional interpretation were facilitated by an updated version of DEGenes Hunter. Acute exposure of both drugs triggered an intense, specific and transient response at 24 h but with hardly observable differences after 48 h at least in the DEAB treatments. Activation of RA signalling by TTNPB specifically increased the expression of genes in pathways related to RA degradation, retinol storage, carotenoid metabolism, homeostatic response and visual cycle, and also modified the expression of transcripts related to morphogenesis and collagen fibril organisation. In contrast, DEAB mainly decreased genes related to retinal production, impairing phototransduction signalling in the retina. A total of 755 transcripts mainly related to lipid metabolism, lipid transport and lipid homeostasis were altered in response to both treatments, indicating non-specific drug responses associated with intestinal absorption. These results indicate that a new assembling and transcript sieving were both necessary to provide a reliable transcriptome to identify the many aspects of RA action during sole development that are of relevance for sole aquaculture.

Acrylamide alters CREB and retinoic acid signalling pathways during differentiation of the human neuroblastoma SH-SY5Y cell line

Acrylamide (ACR) is a known neurotoxicant which crosses the blood–brain barrier, passes the placenta and has been detected in breast milk. Hence, early-life exposure to ACR could lead to developmental neurotoxicity. The aim of this study was to elucidate if non-cytotoxic concentrations of ACR alter neuronal differentiation by studying gene expression of markers significant for neurodevelopment in the human neuroblastoma SH-SY5Y cell model. Firstly, by using RNASeq we identified two relevant pathways that are activated during 9 days of retinoic acid (RA) induced differentiation i.e. RA receptor (RAR) activation and the cAMP response element-binding protein (CREB) signalling pathways. Next, by qPCR we showed that 1 and 70 µM ACR after 9 days exposure alter the expression of 13 out of 36 genes in the RAR activation pathway and 18 out of 47 in the CREB signalling pathway. Furthermore, the expression of established neuronal markers i.e. BDNF, STXBP2, STX3, TGFB1 and CHAT were down-regulated. Decreased protein expression of BDNF and altered ratio of phosphorylated CREB to total CREB were confirmed by western blot. Our results reveal that micromolar concentrations of ACR sustain proliferation, decrease neurite outgrowth and interfere with signalling pathways involved in neuronal differentiation in the SH-SY5Y cell model.