title: Minimal amounts of kindlin-3 suffice for basal platelet and leukocyte functions in mice.
abstract: Hematopoietic cells depend on integrin-mediated adhesion and signaling, which is induced by kindlin-3 and talin-1. To determine whether platelet and polymorphonuclear neutrophil (PMN) functions require specific thresholds of kindlin-3, we generated mouse strains expressing 50%, 10%, or 5% of normal kindlin-3 levels. We report that in contrast to kindlin-3-null mice, which die perinatally of severe bleeding and leukocyte adhesion deficiency, mice expressing as little as 5% of kindlin-3 were viable and protected from spontaneous bleeding and infections. However, platelet adhesion and aggregation were reduced in vitro and bleeding times extended. Similarly, leukocyte adhesion, extravasation, and bacterial clearance were diminished. Quantification of protein copy numbers revealed stoichiometric quantities of kindlin-3 and talin-1 in platelets and neutrophils, indicating that reduction of kindlin-3 in our mouse strains progressively impairs the cooperation with talin-1. Our findings show that very low levels of kindlin-3 enable basal platelet and neutrophil functions, whereas in stress situations such as injury and infection, platelets and neutrophils require a maximum of functional integrins that is achieved with high and stoichiometric quantities of kindlin-3 and talin-1.
authors.affiliation: Max-Planck-Institute of Biochemistry, Department of Molecular Medicine, Martinsried, Germany; Walter Brendel Center for Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany;
authors.forename: Sarah
authors.initials: S
authors.lastname: Klapproth
authors.affiliation: Max-Planck-Institute of Biochemistry, Department of Molecular Medicine, Martinsried, Germany;
authors.forename: Federico A
authors.initials: FA
authors.lastname: Moretti
authors.affiliation: Max-Planck-Institute of Biochemistry, Department of Proteomics and Signal Transduction, Martinsried, Germany; and.
authors.forename: Marlis
authors.initials: M
authors.lastname: Zeiler
authors.affiliation: Max-Planck-Institute of Biochemistry, Department of Molecular Medicine, Martinsried, Germany;
authors.forename: Raphael
authors.initials: R
authors.lastname: Ruppert
authors.affiliation: Max von Pettenkofer-Institute for Hygiene and Medical Microbiology, and.
authors.forename: Ute
authors.initials: U
authors.lastname: Breithaupt
authors.affiliation: Institute for Pathology, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Susanna
authors.initials: S
authors.lastname: Mueller
authors.affiliation: Max von Pettenkofer-Institute for Hygiene and Medical Microbiology, and.
authors.forename: Rainer
authors.initials: R
authors.lastname: Haas
authors.affiliation: Max-Planck-Institute of Biochemistry, Department of Proteomics and Signal Transduction, Martinsried, Germany; and.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mann
authors.affiliation: Walter Brendel Center for Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany;
authors.forename: Markus
authors.initials: M
authors.lastname: Sperandio
authors.affiliation: Max-Planck-Institute of Biochemistry, Department of Molecular Medicine, Martinsried, Germany;
authors.forename: Reinhard
authors.initials: R
authors.lastname: Fässler
authors.affiliation: Max-Planck-Institute of Biochemistry, Department of Molecular Medicine, Martinsried, Germany;
authors.forename: Markus
authors.initials: M
authors.lastname: Moser
mesh_terms: D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000737:chemistry / Q000502:physiology*; D002448:Cell Adhesion; D003598:Cytoskeletal Proteins / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005756:Gastritis / Q000097:blood / Q000276:immunology / Q000382:microbiology; D016481:Helicobacter Infections / Q000097:blood / Q000276:immunology / Q000382:microbiology; D016480:Helicobacter pylori / Q000276:immunology / Q000302:isolation & purification; D006474:Hemorrhagic Disorders / Q000235:genetics; D039641:Integrin beta Chains / Q000502:physiology; D007962:Leukocytes / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009504:Neutrophils / Q000737:chemistry / Q000276:immunology; D010587:Phagocytosis / Q000235:genetics; D010973:Platelet Adhesiveness / Q000235:genetics; D010974:Platelet Aggregation / Q000235:genetics; D016608:Talin / Q000097:blood / Q000235:genetics
chemical_list: D003598:Cytoskeletal Proteins; D039641:Integrin beta Chains; D016608:Talin; C527818:kindlin-3 protein, mouse; C496077:Tln1 protein, mouse