Menu

Close

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

Preprint posted on March 04, 2018 https://www.biorxiv.org/content/early/2018/03/04/276170

Newly discovered human-specific NODAL variant expression downregulates LIFR in human stem cells

Selected by Pierre Osteil

Categories: developmental biology

Background:

NODAL is a growth factor of the TGF-β signalling superfamily that plays critical roles during embryogenesis (particularly in the establishment of left-right asymmetry) and in the maintenance of cancer cells. NODAL has been studied extensively in vertebrate development and in stem cells (1) but this is the first study showing a human-specific splice variant. This article is a follow up study of a previous preprint by the same group (2) relating the discovery of several NODAL splice variants (including an antisense and a circular transcripts) indicating that a lot remains to discover about how NODAL is regulated and affects its targets. Here the authors elucidate a possible function of one of the splice variants that could be involved in the discrepancies observed between naïve and primed embryonic stem cells.

 

The data

In this study, the authors describe one splice variant resulting from a human specific Single Nucleotide Polymorphism (SNP) in the second intron of NODAL (rs2231947 C/T). This intron leads to a transcript that contains a supplementary exon and a Premature Termination Codon, resulting in the translation of a distinct protein. Using morpholinos, they were able to inhibit specifically this variant in human embryonic stem cells (hESC), which led to an increase of Leukemia Inhibitory Factor Receptor (LIFR). Its expression is generally shut down in hESC conversely to mouse species. Both constitutive and human-specific transcripts were injected into zebrafish embryos to assess canonical NODAL signalling activity. While the constitutive NODAL injection leads to a disruption of gastrulation, the variant did not, suggesting different action mechanisms. Moreover, the alternative splicing of NODAL leads to partial disruption of the TGB-β superfamily domain that may impact on NODAL signalling.

Finally, the authors found that the two proteins are differently N-glycosylated, resulting in an increased level of excretion of the variant protein compared to the constitutive NODAL. Differential secretion may thus partially explain their different functions.

Image reproduced from Findlay et al., 2018 Fig 3A and 3B

 

Why did I choose this article?

The newly described NODAL variant could be responsible for the loss of LIFR observed in primed ESCs of non-murine species. The SNP is specific to the human genome and might explain why human stem cells cannot be stabilised at the naïve state of pluripotency. My PhD project was articulated around the understanding of naïve versus primed pluripotency, and I highlighted this article for the clues it gives toward deciphering pluripotency regulatory mechanisms.

 

Open questions

  • Have you checked hESC pluripotency status when the NODAL variant is knocked down? Could you observe upregulation of genes associated to naïve pluripotency?
  • Is this variant present in other mammals such as rabbit or monkey? If yes, you might be able to link the presence of this variant to the impossibility of establishing naïve pluripotency in non-murine mammals?

 

Related research

  1. Pauklin S, Vallier L (2015) Activin/Nodal signalling in stem cells. Development 142(4):607–619.
  2. Findlay SD, Postovit L-M (2018) Comprehensive characterization of transcript diversity at the human NODAL locus. bioRxiv:1–26.

 

Tags: hesc, naive, nodal, primed, stem cell

Posted on: 3rd April 2018

Read preprint (No Ratings Yet)




Have your say

Your email address will not be published. Required fields are marked *

This site uses Akismet to reduce spam. Learn how your comment data is processed.

Sign up to customise the site to your preferences and to receive alerts

Register here

preLists in the developmental biology category:

EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)

A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.

 



List by Alex Eve

EMBL Conference: From functional genomics to systems biology

Preprints presented at the virtual EMBL conference "from functional genomics and systems biology", 16-19 November 2020

 



List by Jesus Victorino

Single Cell Biology 2020

A list of preprints mentioned at the Wellcome Genome Campus Single Cell Biology 2020 meeting.

 



List by Alex Eve

Society for Developmental Biology 79th Annual Meeting

Preprints at SDB 2020

 



List by Irepan Salvador-Martinez, Martin Estermann

FENS 2020

A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020

 



List by Ana Dorrego-Rivas

Planar Cell Polarity – PCP

This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.

 



List by Ana Dorrego-Rivas

Cell Polarity

Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.

 



List by Yamini Ravichandran

TAGC 2020

Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20

 



List by Maiko Kitaoka, Madhuja Samaddar, Miguel V. Almeida, Sejal Davla, Jennifer Ann Black, Dey Lab

3D Gastruloids

A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Preprint missing? Don't hesitate to let us know.

 



List by Paul Gerald L. Sanchez and Stefano Vianello

ASCB EMBO Annual Meeting 2019

A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)

 



List by Madhuja Samaddar, Ramona Jühlen, Amanda Haage, Laura McCormick, Maiko Kitaoka

EDBC Alicante 2019

Preprints presented at the European Developmental Biology Congress (EDBC) in Alicante, October 23-26 2019.

 



List by Sergio Menchero, Jesus Victorino, Teresa Rayon, Irepan Salvador-Martinez

EMBL Seeing is Believing – Imaging the Molecular Processes of Life

Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019

 



List by Dey Lab

SDB 78th Annual Meeting 2019

A curation of the preprints presented at the SDB meeting in Boston, July 26-30 2019. The preList will be updated throughout the duration of the meeting.

 



List by Alex Eve

Lung Disease and Regeneration

This preprint list compiles highlights from the field of lung biology.

 



List by Rob Hynds

Young Embryologist Network Conference 2019

Preprints presented at the Young Embryologist Network 2019 conference, 13 May, The Francis Crick Institute, London

 



List by Alex Eve

Pattern formation during development

The aim of this preList is to integrate results about the mechanisms that govern patterning during development, from genes implicated in the processes to theoritical models of pattern formation in nature.

 



List by Alexa Sadier

BSCB/BSDB Annual Meeting 2019

Preprints presented at the BSCB/BSDB Annual Meeting 2019

 



List by Dey Lab

Zebrafish immunology

A compilation of cutting-edge research that uses the zebrafish as a model system to elucidate novel immunological mechanisms in health and disease.

 



List by Shikha Nayar
Close