title: CLEC-2 and Syk in the megakaryocytic/platelet lineage are essential for development.
abstract: The C-type lectin receptor CLEC-2 signals through a pathway that is critically dependent on the tyrosine kinase Syk. We show that homozygous loss of either protein results in defects in brain vascular and lymphatic development, lung inflation, and perinatal lethality. Furthermore, we find that conditional deletion of Syk in the hematopoietic lineage, or conditional deletion of CLEC-2 or Syk in the megakaryocyte/platelet lineage, also causes defects in brain vascular and lymphatic development, although the mice are viable. In contrast, conditional deletion of Syk in other hematopoietic lineages had no effect on viability or brain vasculature and lymphatic development. We show that platelets, but not platelet releasate, modulate the migration and intercellular adhesion of lymphatic endothelial cells through a pathway that depends on CLEC-2 and Syk. These studies found that megakaryocyte/platelet expression of CLEC-2 and Syk is required for normal brain vasculature and lymphatic development and that platelet CLEC-2 and Syk directly modulate lymphatic endothelial cell behavior in vitro.
authors.affiliation: Centre for Cardiovascular Sciences, Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Brenda A
authors.initials: BA
authors.lastname: Finney
authors.forename: Edina
authors.initials: E
authors.lastname: Schweighoffer
authors.forename: Leyre
authors.initials: L
authors.lastname: Navarro-Núñez
authors.forename: Cecile
authors.initials: C
authors.lastname: Bénézech
authors.forename: Francesca
authors.initials: F
authors.lastname: Barone
authors.forename: Craig E
authors.initials: CE
authors.lastname: Hughes
authors.forename: Stacey A
authors.initials: SA
authors.lastname: Langan
authors.forename: Kate L
authors.initials: KL
authors.lastname: Lowe
authors.forename: Alice Y
authors.initials: AY
authors.lastname: Pollitt
authors.forename: Diego
authors.initials: D
authors.lastname: Mourao-Sa
authors.forename: Steve
authors.initials: S
authors.lastname: Sheardown
authors.forename: Gerard B
authors.initials: GB
authors.lastname: Nash
authors.forename: Nicholas
authors.initials: N
authors.lastname: Smithers
authors.forename: Caetano
authors.initials: C
authors.lastname: Reis e Sousa
authors.forename: Victor L J
authors.initials: VL
authors.lastname: Tybulewicz
authors.forename: Steve P
authors.initials: SP
authors.lastname: Watson
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001792:Blood Platelets / Q000378:metabolism* / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D019070:Cell Lineage / Q000235:genetics* / Q000502:physiology; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental; D048788:Growth and Development / Q000235:genetics* / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008533:Megakaryocytes / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011247:Pregnancy; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000072377:Syk Kinase; D034061:Thrombopoiesis / Q000235:genetics / Q000502:physiology
chemical_list: C529518:CLEC-2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse