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Genetically regulated human NODAL splice variants are differentially post-transcriptionally processed and functionally distinct

Scott D Findlay, Olena Bilyk, Kiefer Lypka, View ORCID ProfileAndrew J Waskiewicz, View ORCID ProfileLynne-Marie Postovit
doi: https://doi.org/10.1101/276170
Scott D Findlay
1University of Alberta. Edmonton, Alberta, Canada. Department of Oncology, Faculty of Medicine and Dentistry
2The University of Western Ontario. London, Ontario, Canada. Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry
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Olena Bilyk
1University of Alberta. Edmonton, Alberta, Canada. Department of Oncology, Faculty of Medicine and Dentistry
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Kiefer Lypka
1University of Alberta. Edmonton, Alberta, Canada. Department of Oncology, Faculty of Medicine and Dentistry
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Andrew J Waskiewicz
3University of Alberta. Edmonton, Alberta, Canada. Department of Biological Sciences, Faculty of Science
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Lynne-Marie Postovit
1University of Alberta. Edmonton, Alberta, Canada. Department of Oncology, Faculty of Medicine and Dentistry
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  • For correspondence: postovit@ualberta.ca
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Abstract

NODAL is a morphogen essential for early embryonic development in vertebrates. Since much of our understanding of NODAL comes from model organisms, we aimed to directly assess post-transcriptional regulation of human NODAL with specific attention to a newly discovered human-specific NODAL splice variant. Selective depletion of the NODAL variant in human embryonic stem cells resulted in increased LIFR levels, while total NODAL knockdown resulted in a decrease of several markers of pluripotency. The NODAL variant did not transmit a canonical NODAL signal in zebrafish embryos, but may share some functional capability with canonical NODAL in cancer cells. At the protein level, disruption of disulfide bond formation dramatically enhanced proteolytic processing of NODAL. Disruption of NODAL N-glycosylation decreased its secretion but not extracellular stability, and a novel N-glycosylation in the NODAL variant contributed to enhanced secretion. Collectively, this work offers a direct and precise account of post-transcriptional regulation of human NODAL.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted March 04, 2018.
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Genetically regulated human NODAL splice variants are differentially post-transcriptionally processed and functionally distinct
Scott D Findlay, Olena Bilyk, Kiefer Lypka, Andrew J Waskiewicz, Lynne-Marie Postovit
bioRxiv 276170; doi: https://doi.org/10.1101/276170
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Genetically regulated human NODAL splice variants are differentially post-transcriptionally processed and functionally distinct
Scott D Findlay, Olena Bilyk, Kiefer Lypka, Andrew J Waskiewicz, Lynne-Marie Postovit
bioRxiv 276170; doi: https://doi.org/10.1101/276170

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