Genetically regulated human NODAL splice variants are differentially post-transcriptionally processed and functionally distinct
Preprint posted on 4 March 2018 https://www.biorxiv.org/content/early/2018/03/04/276170
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.
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.
- 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?
- Pauklin S, Vallier L (2015) Activin/Nodal signalling in stem cells. Development 142(4):607–619.
- Findlay SD, Postovit L-M (2018) Comprehensive characterization of transcript diversity at the human NODAL locus. bioRxiv:1–26.
Posted on: 3 April 2018Read preprint
Also in the developmental biology category:
Learning a conserved mechanism for early neuroectoderm morphogenesis
The genetic basis of novel trait gain in walking fish
Nanos2+ cells give rise to germline and somatic lineages in the sea anemone Nematostella vectensis
preListsdevelopmental biology category:in the
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
|Alex Eve, Katherine Brown
preLights peer support – preprints of interest
This is a preprint repository to organise the preprints and preLights covered through the 'preLights peer support' initiative.
|preLights peer support
The Society for Developmental Biology 82nd Annual Meeting
This preList is made up of the preprints discussed during the Society for Developmental Biology 82nd Annual Meeting that took place in Chicago in July 2023.
|Joyce Yu, Katherine Brown
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
Journal of Cell Science meeting ‘Imaging Cell Dynamics’
This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
|Sergio Menchero et al.
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
|Nadja Hümpfer et al.
2nd Conference of the Visegrád Group Society for Developmental Biology
Preprints from the 2nd Conference of the Visegrád Group Society for Developmental Biology (2-5 September, 2021, Szeged, Hungary)
The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
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
Single Cell Biology 2020
A list of preprints mentioned at the Wellcome Genome Campus Single Cell Biology 2020 meeting.
Society for Developmental Biology 79th Annual Meeting
Preprints at SDB 2020
|Irepan Salvador-Martinez, Martin Estermann
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
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.
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.
Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20
|Maiko Kitaoka et al.
A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.
|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)
|Madhuja Samaddar et al.
EDBC Alicante 2019
Preprints presented at the European Developmental Biology Congress (EDBC) in Alicante, October 23-26 2019.
|Sergio Menchero et al.
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
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.
Lung Disease and Regeneration
This preprint list compiles highlights from the field of lung biology.
Young Embryologist Network Conference 2019
Preprints presented at the Young Embryologist Network 2019 conference, 13 May, The Francis Crick Institute, London
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.
BSCB/BSDB Annual Meeting 2019
Preprints presented at the BSCB/BSDB Annual Meeting 2019
A compilation of cutting-edge research that uses the zebrafish as a model system to elucidate novel immunological mechanisms in health and disease.