Phospholipase Cγ2 is necessary for separation of blood and lymphatic vasculature in mice

Ichise, Hirotake; Ichise, Taeko; Ohtani, Osamu; Yoshida, Nobuaki

doi:10.1242/dev.025353

Cited by 99Lymphatic System and DiseasesLymphatic Disorders and TreatmentsDevelopmental Biology and Gene Regulation

Phospholipase Cγ2 is necessary for separation of blood and lymphatic vasculature in mice

Ichise, Hirotake, Ichise, Taeko, Ohtani, Osamu, Yoshida, Nobuaki·2009·Development

DOI 10.1242/dev.025353

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Abstract

The lymphatic vasculature originates from the blood vasculature through a mechanism relying on Prox1 expression and VEGFC signalling, and is separated and kept separate from the blood vasculature in a Syk- and SLP76-dependent manner. However, the mechanism by which lymphatic vessels are separated from blood vessels is not known. To gain an understanding of the vascular partitioning, we searched for the affected gene in a spontaneous mouse mutant exhibiting blood-filled lymphatic vessels, and identified a null mutation of the Plcg2 gene, which encodes phospholipase Cγ2 (PLCγ2),by positional candidate cloning. The blood-lymph shunt observed in PLCγ2-null mice was due to aberrant separation of blood and lymphatic vessels. A similar phenotype was observed in lethally irradiated wild-type mice reconstituted with PLCγ2-null bone marrow cells. These findings indicate that PLCγ2 plays an essential role in initiating and maintaining the separation of the blood and lymphatic vasculature.

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Previous studies have reported internal hemorrhaging during development in other Plcg2 deficient mouse models, which have been proposed to be caused by rupture of blood-filled fragile lymphatic vessels by mechanical stress or pressure of the blood flow.
“Previous studies have reported internal hemorrhaging during development in other Plcg2 deficient mouse models (29, 30), which have been proposed to be caused by rupture of blood-filled fragile lymphatic vessels by mechanical stress or pressure of the blood flow (29).”
From Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain (2023) · cites this paper as [29]
The cause of death was not determined but may be related to the previously described essential role of PLCγ2 in initiating the separation of the blood and lymphatic vasculature.
“The cause of death was not determined but may be related to the previously described essential role of PLCγ2 in initiating the separation of the blood and lymphatic vasculature (29).”
From Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain (2023) · cites this paper as [29]
PLCγ2 is necessary for separation of blood and lymphatic vessels in mice and osteoclastogenesis, and PLCγ2 outside of the brain has roles in immune deficiencies, autoimmunity, and cancer.
“PLCγ2 is necessary for separation of blood and lymphatic vessels in mice (29) and osteoclastogenesis (42), and PLCγ2 outside of the brain has roles in immune deficiencies, autoimmunity, and cancer (18).”
From Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain (2023) · cites this paper as [29]
In different models of PLCG2 depletion, homozygous knockout embryos were found to have significant subcutaneous hemorrhaging, suggesting impacted vascular development and bleeding that may underlie embryonic death and reduced frequencies at weaning.
“In different models of PLCG2 depletion, homozygous knockout embryos were found to have significant subcutaneous hemorrhaging, suggesting impacted vascular development and bleeding that may underlie embryonic death and reduced frequencies at weaning.”
From PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology (2025) · cites this paper as [44]

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“19,44 Previous studies have also identified significantly reduced birth rates of mice deficient in PLCG2, with females being more significantly impacted.”
PLC γ2 promotes apoptosis while inhibits proliferation in rat hepatocytes through PKCD / JNK MAPK and PKCD /p38 MAPK signalling
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CLEC‐2‐dependent activation of mouse platelets is weakly inhibited by cAMP but not by cGMP
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Low Efficacy of Genetic Tests for the Diagnosis of Primary Lymphedema Prompts Novel Insights into the Underlying Molecular Pathways
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Loss of Arnt (Hif1β) in mouse epidermis triggers dermal angiogenesis, blood vessel dilation and clotting defects
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Mouse podoplanin supports adhesion and aggregation of platelets under arterial shear: A novel mechanism of haemostasis
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Self-citation
Platelets
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“Previous studies have reported internal hemorrhaging during development in other Plcg2 deficient mouse models (29, 30), which have been proposed to be caused by rupture of blood-filled fragile lymphatic vessels by mechanical stress or pressure of the blood flow (29).”
Background
GPVI and CLEC-2
Haining, E. J., Nicolson, P. L. R., Onselaer, M.-B., Poulter, N. S., Rayes, J., Thomas, M. R., & Watson, S. P. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-813456-6.00011-4 · Cited by 4 · see citing works
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Phospholipases: Paving the Way for a New Life
Kumar, R., Vats, P., Panchal, P., & Kumar, S. (2025) · Reproductive Sciences · doi:10.1007/s43032-025-01900-z · Cited by 2 · see citing works
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The Role of Platelets in Lymphangiogenesis and Neoangiogenesis
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Alzheimer's Protection by <scp>PLCγ2</scp> Compacts Plaques, Redistributes Microglia, and Protects Synapses in <scp> App NL </scp> ‐G‐F Mice
Bevan, R. J., Maguire, E., Mackinnon, E., Salis, E., Phillips, T., Simonazzi, E., Vassileva, M., Allen, N. D., Williams, J., & Taylor, P. R. (2026) · Glia · doi:10.1002/glia.70192 · Cited by 1 · see citing works
Platelet CLEC-2
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Platelet Membrane Receptors and Signalling Pathways
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PLCγ2 deficiency compromises systemic immune tolerance and erodes myelin homeostasis while enhancing oxidative metabolism in the mouse brain
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Tratamento com VEGFC para revascularização linfática em membros pélvicos de camundongos
Paulo, S. (2013)
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CLEC-2
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CLEC-2
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Literature Watch
Blei, F. (2009) · Lymphatic Research and Biology · doi:10.1089/lrb.2009.7102
CLEC-2
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血管とリンパ管が独立したネットワークを構築する原理の解明
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Authors: Ichise, H., Ichise, T., Ohtani, O., & Yoshida, N.
Affiliations: Institute of Medical Science, The University of Tokyo (JP)
University of Toyama (JP)
ORCID: Ichise, Hirotake
Ichise, Taeko
Yoshida, Nobuaki
Venue: Development
Publisher: The Company of Biologists
Published: 2009-01-15
Volume: 136
Issue: 2
Pages: 191-195
ISSN: 0950-1991 (ISSN-L)
1477-9129
DOI: 10.1242/dev.025353
OpenAlex: W2116298485
Cited by: 98
References: 19
Citations by year: 2026: 2 · 2025: 5 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 2 · 2020: 5 · 2019: 5 · 2018: 2 · 2017: 8 · 2016: 9 · 2015: 4 · 2014: 11 · 2013: 7 · 2012: 7
FWCI: 4.58
Type: journal article
Language: en
Open access: closed
Locations: Development (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
Health Sciences › Medicine › Surgery › Lymphatic Disorders and Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords: PLCγ2, lymphatic vessels, lymphatic development, Prox1, Syk, SLP-76, bone marrow reconstitution
MeSH terms: Animals, Base Sequence, Blood Vessels, Cells, Cultured, Female, Humans, Mice, Mutant Strains, Mice, Transgenic, Polymorphism, Genetic, Pregnancy, Radiation Chimera, Bone Marrow Transplantation, DNA Primers, Mice, Knockout, Lymphatic Vessels, Endothelial Cells, Mice, Phospholipase C gamma

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Phospholipase Cγ2 is necessary for separation of blood and lymphatic vasculature in mice

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