title: Loss of the F-BAR protein CIP4 reduces platelet production by impairing membrane-cytoskeleton remodeling.
abstract: Megakaryocytes generate platelets through extensive reorganization of the cytoskeleton and plasma membrane. Cdc42 interacting protein 4 (CIP4) is an F-BAR protein that localizes to membrane phospholipids through its BAR domain and interacts with Wiskott-Aldrich Syndrome Protein (WASP) via its SRC homology 3 domain. F-BAR proteins promote actin polymerization and membrane tubulation. To study its function, we generated CIP4-null mice that displayed thrombocytopenia similar to that of WAS(-) mice. The number of megakaryocytes and their progenitors was not affected. However, the number of proplatelet protrusions was reduced in CIP4-null, but not WAS(-), megakaryocytes. Electron micrographs of CIP4-null megakaryocytes showed an altered demarcation membrane system. Silencing of CIP4, not WASP, expression resulted in fewer proplatelet-like extensions. Fluorescence anisotropy studies showed that loss of CIP4 resulted in a more rigid membrane. Micropipette aspiration demonstrated decreased cortical actin tension in megakaryocytic cells with reduced CIP4 or WASP protein. These studies support a new biophysical mechanism for platelet biogenesis whereby CIP4 enhances the complex, dynamic reorganization of the plasma membrane (WASP independent) and actin cortex network (as known for WASP and cortical actin) to reduce the work required for generating proplatelets. CIP4 is a new component in the highly coordinated system of megakaryocytic membrane and cytoskeletal remodeling affecting platelet production.
authors.affiliation: Department of Pediatrics, Robert H. Lurie Comprehensive Cancer Center and Children's Memorial Hospital, Northwestern Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Yolande
authors.initials: Y
authors.lastname: Chen
authors.forename: Jorie
authors.initials: J
authors.lastname: Aardema
authors.forename: Sayali
authors.initials: S
authors.lastname: Kale
authors.forename: Zakary L
authors.initials: ZL
authors.lastname: Whichard
authors.forename: Arinola
authors.initials: A
authors.lastname: Awomolo
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Blanchard
authors.forename: Brian
authors.initials: B
authors.lastname: Chang
authors.forename: David R
authors.initials: DR
authors.lastname: Myers
authors.forename: Lining
authors.initials: L
authors.lastname: Ju
authors.forename: Reginald
authors.initials: R
authors.lastname: Tran
authors.forename: David
authors.initials: D
authors.lastname: Reece
authors.forename: Hilary
authors.initials: H
authors.lastname: Christensen
authors.forename: Siham
authors.initials: S
authors.lastname: Boukour
authors.forename: Najet
authors.initials: N
authors.lastname: Debili
authors.forename: Ted S
authors.initials: TS
authors.lastname: Strom
authors.forename: David
authors.initials: D
authors.lastname: Rawlings
authors.forename: Francisco X
authors.initials: FX
authors.lastname: Vázquez
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Voth
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhu
authors.forename: Walter H A
authors.initials: WH
authors.lastname: Kahr
authors.forename: Wilbur A
authors.initials: WA
authors.lastname: Lam
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Corey
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D001696:Biomechanical Phenomena; D001792:Blood Platelets / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D003114:Colony-Forming Units Assay; D003599:Cytoskeleton / Q000378:metabolism*; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D008297:Male; D008533:Megakaryocytes / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008560:Membrane Fluidity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000378:metabolism*; D015778:Minor Histocompatibility Antigens; D011003:Ploidies; D021381:Protein Transport; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D013921:Thrombocytopenia / Q000378:metabolism / Q000473:pathology; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000378:metabolism
chemical_list: D008869:Microtubule-Associated Proteins; D015778:Minor Histocompatibility Antigens; C485787:Trip10 protein, mouse; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal