β4GALT1 controls β1 integrin function to govern thrombopoiesis and hematopoietic stem cell homeostasis. Nat Commun 2020 Jan 17;11(1):356
Date
01/19/2020Pubmed ID
31953383Pubmed Central ID
PMC6968998DOI
10.1038/s41467-019-14178-yScopus ID
2-s2.0-85078016291 (requires institutional sign-in at Scopus site) 33 CitationsAbstract
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.
Author List
Giannini S, Lee-Sundlov MM, Rivadeneyra L, Di Buduo CA, Burns R, Lau JT, Falet H, Balduini A, Hoffmeister KMAuthors
Herve Falet PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinKarin Hoffmeister MD Professor in the Biochemistry department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsBlood 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
