The protein phosphatase 2A B56γ regulatory subunit is required for heart development
Open accessAbstract
BACKGROUND: Protein Phosphatase 2A (PP2A) function is controlled by regulatory subunits that modulate the activity of the catalytic subunit and direct the PP2A complex to specific intracellular locations. To study PP2A's role in signal transduction pathways that control growth and differentiation in vivo, a transgenic mouse lacking the B56γ regulatory subunit of PP2A was made. RESULTS: Lack of PP2A activity specific to the PP2A-B56γ holoenzyme, resulted in the formation of an incomplete ventricular septum and a decrease in the number of ventricular cardiomyocytes. During cardiac development, B56γ is expressed in the nucleus of α-actinin-positive cardiomyocytes that contain Z-bands. The pattern of B56γ expression correlated with the cardiomyocyte apoptosis we observed in B56γ-deficient mice during mid to late gestation. In addition to the cardiac phenotypes, mice lacking B56γ have a decrease in locomotive coordination and gripping strength, indicating that B56γ has a role in controlling PP2A activity required for efficient neuromuscular function. CONCLUSIONS: PP2A-B56γ activity is required for efficient cardiomyocyte maturation and survival. The PP2A B56γ regulatory subunit controls PP2A substrate specificity in vivo in a manner that cannot be fully compensated for by other B56 subunits.
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B56γ is critical for heart development; B56γ−/− mice show increased neonatal death and ventricular septal defects from E16 due to apoptosis.
“In addition, B56γ is also critical for heart development. Although not embryonic lethal, B56γ−/− leads to increased neonatal death in mice. Starting from E16, B56γ−/− mice exhibit ventricular septal defects in the heart due to increased apoptosis (Varadkar et al., 2014).”
From PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer (2019) · cites this paper as Varadkar et al., 2014
B56γ knockout mice showed increased neonatal death at P1-P2, were less active, and were smaller than wild-type littermates.
“These mice showed increased neonatal death (P1-P2), were less active and smaller in mass than their WT littermates.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [67]
Some heart phenotypes seen in AΔ5 transgenic mice were also found in mice with total-body constitutive knockout of Ppp2r5c, encoding B56γ.
“some of the heart phenotypes seen in AΔ5 transgenic mice, were also found in mice with a total-body, constitutive KO of Ppp2r5c, encoding the B56γ subunits.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [67]
Surviving mice in the constitutive total-body Ppp2r5c knockout model became obese, with 30% increased body weights and increased white adipose tissue.
“the surviving mice in the constitutive total-body KO model of Ppp2r5c (encoding the B56γ subunits) became obese, exhibiting 30% increased body weights and increased amounts of white adipose tissue [67].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [67]
This B56γ knockout phenotype was attributed to increased cardiomyocytic apoptosis.
“This phenotype was attributed to increased cardiomyocytic apoptosis [67].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [67]
B56γ knockout hearts had significantly thinner ventricular walls and less ventricular tissue, with total lack of a ventricular septum in half of fetuses at E16.5.
“In their hearts, significantly thinner ventricular walls and less ventricular tissue were seen, with total lack of a ventricular septum observed in half of the B56γ KO fetuses at E16.5.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [67]
Surviving adult B56γ knockout mice also showed significantly thinner septums.
“Surviving adult mice also showed significantly thinner septums.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [67]
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References 31 · Cited by 34
- Authors
- Varadkar, P., Despres, D., Kraman, M., Lozier, J., Phadke, A., Nagaraju, K., & Mccright, B.
- Affiliations
- Center for Biologics Evaluation and Research (US)
- National Institutes of Health (US)
- University of Cambridge (GB)
- Children's National (US)
- Corresponding author
- Mccright, Brent
- Venue
- Developmental Dynamics
- Publisher
- Wiley
- Published
- 2014-02-18
- Volume
- 243
- Issue
- 6
- Pages
- 778-790
- ISSN
- 1058-8388 (ISSN-L)
- 1097-0177
- OpenAlex
- W1812584421
- Cited by
- 34
- References
- 31
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 3 · 2020: 3 · 2019: 4 · 2018: 4 · 2017: 5 · 2016: 1 · 2015: 3 · 2014: 1
- FWCI
- 1.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Developmental Dynamics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- protein phosphatase 2A, heart development, cardiomyocyte apoptosis, cardiomyocyte maturation, cardiomyocyte survival, neuromuscular function, substrate specificity, transgenic knockout mice, Z-band
- MeSH terms
- Animals, Embryo, Mammalian, Heart Septum, Heart Ventricles, Mice, Obese, Mice, Knockout, Myocytes, Cardiac, Mice, Protein Phosphatase 2
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