Patterning and gastrulation defects caused by the tw18 lethal are due to loss of Ppp2r1a
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ABSTRACT The mouse t haplotype, a variant 20 cM genomic region on Chromosome 17, harbors 16 embryonic control genes identified by recessive lethal mutations isolated from wild mouse populations. Due to technical constraints so far only one of these, the tw5 lethal, has been cloned and molecularly characterized. Here we report the molecular isolation of the tw18 lethal. Embryos carrying the tw18 lethal die from major gastrulation defects commencing with primitive streak formation at E6.5. We have used transcriptome and marker gene analyses to describe the molecular etiology of the tw18 phenotype. We show that both WNT and Nodal signal transduction are impaired in the mutant epiblast, causing embryonic patterning defects and failure of primitive streak and mesoderm formation. By using a candidate gene approach, gene knockout by homologous recombination and genetic rescue, we have identified the gene causing the tw18 phenotype as Ppp2r1a, encoding the PP2A scaffolding subunit PR65alpha. Our work highlights the importance of phosphatase 2A in embryonic patterning, primitive streak formation, gastrulation, and mesoderm formation downstream of WNT and Nodal signaling.
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Impaired Wnt signaling during development in the t w18 deletion model could be entirely attributed to loss of Ppp2r1a, as re-expression of the full Ppp2r1a gene rescued embryonic lethality at E10.5 and E18.5.
“In line with the disorganized Wnt signaling in Cα KO mice, impaired Wnt signaling during development in this embryonically lethal t w18 deletion model could indeed be entirely attributed to the loss of Ppp2r1a, as re-expression of the full Ppp2r1a gene, including sequences 3 kb upstream and 20 kb downstream of the transcription initiation site, resulted in a complete rescue of the observed Embryo”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [36]
Constitutive knockout of Ppp2r1a in two different models resulted in embryonic lethality between E5 and E10.5.
“In line with the observations from Cα KO mice, constitutive KO of Ppp2r1a in two different models resulted in embryonic lethality between E5 and E10.5 [10,36].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [36]
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Sarais, F., Krempien, F., Koehn, C., Brewing, L., Classen, C. F., Walter, M., & Shokraie, O. (2025) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-025-03560-y · Cited by 8 · see citing works
- Authors
- Lange, L., Marks, M., Liu, J., Wittler, L., Bauer, H., Piehl, S., Bläß, G., Timmermann, B., & Herrmann, B. G.
- Affiliations
- Max Planck Institute for Molecular Genetics (DE)
- Corresponding author
- Herrmann, Bernhard G.
- Venue
- Biology Open
- Publisher
- The Company of Biologists
- Published
- 2017-06-15
- Volume
- 6
- Issue
- 6
- Pages
- 752-764
- ISSN
- 2046-6390 (ISSN-L)
- PMC
- PMC5483016
- OpenAlex
- W2626118834
- Cited by
- 19
- References
- 94
- Citations by year
- 2025: 1 · 2024: 5 · 2022: 4 · 2021: 2 · 2020: 1 · 2019: 1 · 2018: 4 · 2017: 1
- FWCI
- 0.78
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Biology Open (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Max Planck Digital Library (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, cc-by)
- Refubium (Universitätsbibliothek der Freien Universität Berlin) (submittedVersion, cc-by)
- RWTH Publications (RWTH Aachen)
- Funders
- Core
- Max-Planck-Gesellschaft
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- t haplotypes, PPP2R1A, protein phosphatase 2A, embryonic patterning, primitive streak formation, mesoderm formation, Wnt signaling, Nodal signaling, epiblast, gene knockout, genetic rescue
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