Tyrosine phosphatase MEG2 modulates murine development and platelet and lymphocyte activation through secretory vesicle function.
MEG2, a protein tyrosine phosphatase with a unique NH2-terminal lipid-binding domain, binds to and is modulated by the polyphosphoinositides PI(4,5)P2 and PI(3,4,5)P3. Recent data implicate MEG2 in vesicle fusion events in leukocytes. Through the genesis of Meg2-deficient mice, we demonstrate that Meg2-/- embryos manifest hemorrhages, neural tube defects including exencephaly and meningomyeloceles, cerebral infarctions, abnormal bone development, and >90% late embryonic lethality. T lymphocytes and platelets isolated from recombination activating gene 2-/- mice transplanted with Meg2-/- embryonic liver-derived hematopoietic progenitor cells showed profound defects in activation that, in T lymphocytes, was attributable to impaired interleukin 2 secretion. Ultrastructural analysis of these lymphocytes revealed near complete absence of mature secretory vesicles. Taken together, these observations suggest that MEG2-mediated modulation of secretory vesicle genesis and function plays an essential role in neural tube, vascular, and bone development as well as activation of mature platelets and lymphocytes.
Wang
Yingchun
Y
Division of Respirology, Department of Medicine, and the McLaughlin Center for Molecular Medicine, University of Toronto and Toronto General Hospital Research Institute of the University Health Network, Toronto, Ontario M5S 1A8, Canada.
Vachon
Eric
E
Zhang
Jinyi
J
Cherepanov
Vera
V
Kruger
Joshua
J
Li
Jun
J
Saito
Kan
K
Shannon
Patrick
P
Bottini
Nunzio
N
Huynh
Huong
H
Ni
Heyu
H
Yang
Hong
H
McKerlie
Colin
C
Quaggin
Sue
S
Zhao
Zhizhuang Joe
ZJ
Marsden
Philip A
PA
Mustelin
Tomas
T
Siminovitch
Katherine A
KA
Downey
Gregory P
GP
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism / Q000648:ultrastructure; D001846:Bone Development / Q000502:physiology; D002544:Cerebral Infarction / Q000235:genetics / Q000473:pathology; D047108:Embryonic Development / Q000502:physiology*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000648:ultrastructure; D006470:Hemorrhage / Q000235:genetics / Q000473:pathology; D008099:Liver / Q000196:embryology / Q000473:pathology; D008213:Lymphocyte Activation / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology; D009436:Neural Tube Defects / Q000235:genetics / Q000648:ultrastructure; D015539:Platelet Activation / Q000502:physiology*; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D022142:Secretory Vesicles / Q000378:metabolism / Q000648:ultrastructure; D013601:T-Lymphocytes / Q000378:metabolism / Q000648:ultrastructure
D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C507735:Ptpn9 protein, mouse