Dataset Information

A deficiency in SUMOylation activity disrupts multiple pathways leading to neural tube and heart defects in Xenopus embryos.

ABSTRACT: BACKGROUND:Adenovirus protein, Gam1, triggers the proteolytic destruction of the E1 SUMO-activating enzyme. Microinjection of an empirically determined amount of Gam1 mRNA into one-cell Xenopus embryos can reduce SUMOylation activity to undetectable, but nonlethal, levels, enabling an examination of the role of this post-translational modification during early vertebrate development. RESULTS:We find that SUMOylation-deficient embryos consistently exhibit defects in neural tube and heart development. We have measured differences in gene expression between control and embryos injected with Gam1 mRNA at three developmental stages: early gastrula (immediately following the initiation of zygotic transcription), late gastrula (completion of the formation of the three primary germ layers), and early neurula (appearance of the neural plate). Although changes in gene expression are widespread and can be linked to many biological processes, three pathways, non-canonical Wnt/PCP, snail/twist, and Ets-1, are especially sensitive to the loss of SUMOylation activity and can largely account for the predominant phenotypes of Gam1 embryos. SUMOylation appears to generate different pools of a given transcription factor having different specificities with this post-translational modification involved in the regulation of more complex, as opposed to housekeeping, processes. CONCLUSIONS:We have identified changes in gene expression that underlie the neural tube and heart phenotypes resulting from depressed SUMOylation activity. Notably, these developmental defects correspond to the two most frequently occurring congenital birth defects in humans, strongly suggesting that perturbation of SUMOylation, either globally or of a specific protein, may frequently be the origin of these pathologies.

SUBMITTER: Bertke MM

PROVIDER: S-EPMC6525467 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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A deficiency in SUMOylation activity disrupts multiple pathways leading to neural tube and heart defects in Xenopus embryos.

Bertke Michelle M MM Dubiak Kyle M KM Cronin Laura L Zeng Erliang E Huber Paul W PW

BMC genomics 20190517 1

<h4>Background</h4>Adenovirus protein, Gam1, triggers the proteolytic destruction of the E1 SUMO-activating enzyme. Microinjection of an empirically determined amount of Gam1 mRNA into one-cell Xenopus embryos can reduce SUMOylation activity to undetectable, but nonlethal, levels, enabling an examination of the role of this post-translational modification during early vertebrate development.<h4>Results</h4>We find that SUMOylation-deficient embryos consistently exhibit defects in neural tube and ...[more]

PMID: 31101013

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Project description:Environmental teratogens such as smoking are known risk factors for developmental disorders such as cleft palate. While smoking rates have declined, a new type of smoking, called vaping is on the rise. Vaping is the use of e-cigarettes to vaporize and inhale an e-liquid containing nicotine and food-like flavors. There is the potential that, like smoking, vaping could also pose a danger to the developing human. Rather than waiting for epidemiological and mammalian studies, we have turned to an aquatic developmental model, Xenopus laevis, to more quickly assess whether e-liquids contain teratogens that could lead to craniofacial malformations. Xenopus, like zebrafish, has the benefit of being a well-established developmental model and has also been effective in predicting whether a chemical could be a teratogen. We have determined that embryonic exposure to dessert flavored e-liquids can cause craniofacial abnormalities, including an orofacial cleft in Xenopus. To better understand the underlying mechanisms contributing to these defects, transcriptomic analysis of the facial tissues of embryos exposed to a representative dessert flavored e-liquid vapor extract was performed. Analysis of differentially expressed genes in these embryos revealed several genes associated with retinoic acid metabolism or the signaling pathway. Consistently, retinoic acid receptor inhibition phenocopied the craniofacial defects as those embryos exposed to the vapor extract of the e-liquid. Such malformations also correlated with a group of common differentially expressed genes, two of which are associated with midface birth defects in humans. Further, e-liquid exposure sensitized embryos to forming craniofacial malformations when they already had depressed retinoic acid signaling. Moreover, 13-cis-retinoic acid treatment could significantly reduce the e-liquid induced malformation in the midface. Such results suggest the possibility of an interaction between retinoic acid signaling and e-liquid exposure. One of the most popular and concentrated flavoring chemicals in dessert flavored e-liquids is vanillin. Xenopus embryos exposed to this chemical closely resembled embryos exposed to dessert-like e-liquids and a retinoic acid receptor antagonist. In summary, we determined that e-liquid chemicals, in particular vanillin, can cause craniofacial defects potentially by dysregulating retinoic acid signaling. This work warrants the evaluation of vanillin and other such flavoring additives in e-liquids on mammalian development.

Project description:BackgroundNeural tube defects (NTDs) are one of the most common types of birth defects. Oral folic acid (FA) prophylaxis is currently available, but the pathogenesis of NTDs is not fully understood. We conducted this study to examine the role of the immune landscape of NTDs and identify novel diagnostic and therapeutic biomarkers.MethodsWe downloaded the GSE33111 data set of 12 NTD embryos and 12 healthy embryos in the same period of fetal development from the Gene Expression Omnibus (GEO) database. We compared the healthy embryos and NTD embryos to identify the differentially expressed genes (DEGs). We also performed a functional enrichment analysis of the DEGs using the clusterProfiler package. We extracted the top 10 ranked genes as hub immune-related biomarkers. We then used receiver operating characteristic (ROC) curves to determine the expression levels of the hub immune-related genes and the accuracy of the diagnosis of NTDs. Finally, we analyzed the immune landscape of the NTD embryos and healthy embryos via a single-sample gene set enrichment analysis (ssGSEA).ResultsA total of 611 DEGs were identified by the differential analysis, including 95 immune genes. The functional enrichment analysis indicated that Epstein-Barr virus infection, antigen processing and presentation, inflammatory bowel disease, and type I diabetes mellitus were associated with NTDs. The results of the expression level analysis showed that the hub immune-related genes were more highly expressed in the NTD embryos than the healthy embryos. Additionally, the ROC curve analysis also indicated that the expression levels of the 10 hub immune-related genes were highly accurate in the diagnosis of NTDs [area under the curve (AUC) range, 0.708-0.812]. The immune infiltration analysis demonstrated that 20 of the 28 immune cell types were more highly infiltrated in the NTD embryos than the healthy embryos.ConclusionsImmune-related genes are important regulators of the occurrence and development of NTDs.

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A deficiency in SUMOylation activity disrupts multiple pathways leading to neural tube and heart defects in Xenopus embryos.

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A deficiency in SUMOylation activity disrupts multiple pathways leading to neural tube and heart defects in Xenopus embryos.

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