β4GALT1 controls β1 integrin function to govern thrombopoiesis and hematopoietic stem cell homeostasis. Other Scholarly Work

cited authors

  • Giannini, Silvia; Lee-Sundlov, Melissa M; Rivadeneyra, Leonardo; Di Buduo, Christian A; Burns, Robert; Lau, Joseph T; Falet, Hervé; Balduini, Alessandra; Hoffmeister, Karin M

fiu authors

abstract

  • Glycosylation is critical to megakaryocyte (MK) and thrombopoiesis in the context of gene mutations that affect sialylation and galactosylation. Here, we identify the conserved B4galt1 gene as a critical regulator of thrombopoiesis in MKs. β4GalT1 deficiency increases the number of fully differentiated MKs. However, the resulting lack of glycosylation enhances β1 integrin signaling leading to dysplastic MKs with severely impaired demarcation system formation and thrombopoiesis. Platelets lacking β4GalT1 adhere avidly to β1 integrin ligands laminin, fibronectin, and collagen, while other platelet functions are normal. Impaired thrombopoiesis leads to increased plasma thrombopoietin (TPO) levels and perturbed hematopoietic stem cells (HSCs). Remarkably, β1 integrin deletion, specifically in MKs, restores thrombopoiesis. TPO and CXCL12 regulate β4GalT1 in the MK lineage. Thus, our findings establish a non-redundant role for β4GalT1 in the regulation of β1 integrin function and signaling during thrombopoiesis. Defective thrombopoiesis and lack of β4GalT1 further affect HSC homeostasis.

publication date

  • January 17, 2020

keywords

  • Animals
  • Blood Platelets
  • Cell Adhesion
  • Cell Differentiation
  • Chemokine CXCL12
  • Collagen
  • Disease Models, Animal
  • Fibronectins
  • Galactosyltransferases
  • Genetic Predisposition to Disease
  • Hematopoietic Stem Cells
  • Hemorrhage
  • Homeostasis
  • Integrin beta1
  • Laminin
  • Ligands
  • Megakaryocytes
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Signal Transduction
  • Thrombocytopenia
  • Thrombopoiesis
  • Thrombopoietin

Digital Object Identifier (DOI)

Medium

  • Electronic

start page

  • 356

volume

  • 11

issue

  • 1