Dysregulation of erythropoiesis and altered erythroblastic NMDA receptor-mediated calcium influx in Lrfn2-deficient mice
Open Access
- 22 January 2021
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 16 (1), e0245624
- https://doi.org/10.1371/journal.pone.0245624
Abstract
LRFN2 encodes a synaptic adhesion-like molecule that physically interacts with N-methyl-D-aspartate (NMDA) receptor 1 and its scaffold proteins. Previous studies in humans and mice have demonstrated its genetic association with neurodevelopmental disorders such as learning deficiency and autism. In this study, we showed that Lrfn2-deficient (KO) mice exhibit abnormalities of erythropoietic systems due to altered NMDA receptor function. In mature Lrfn2 KO male mice, peripheral blood tests showed multilineage abnormalities, including normocytic erythrocythemia, and reduced platelet volume. Colony forming unit assay using bone marrow cells revealed decreases in the counts of erythrocyte progenitors (CFU-E) as well as granulocytes and monocyte progenitors (CFU-GM). Whole bone marrow cell staining showed that serum erythropoietin (EPO) level was decreased and EPO receptor-like immunoreactivity was increased. Flow cytometry analysis of bone marrow cells revealed increased early erythroblast count and increased transferrin receptor expression in late erythroblasts. Further, we found that late erythroblasts in Lrfn2 KO exhibited defective NMDA receptor-mediated calcium influx, which was inhibited by the NMDA receptor antagonist MK801. These results indicate that Lrfn2 has biphasic roles in hematopoiesis and is associated with the functional integrity of NMDA receptors in hematopoietic cells. Furthermore, taken together with previous studies that showed the involvement of NMDA receptors in hematopoiesis, the results of this study indicate that Lrfn2 may regulate erythropoiesis through its regulatory activity on NMDA receptors.Funding Information
- Ministry of Education, Culture, Sports, Science and Technology (20K21605)
- Ministry of Education, Culture, Sports, Science and Technology (19H03327)
- Ministry of Education, Culture, Sports, Science and Technology (20K06927)
This publication has 35 references indexed in Scilit:
- Erythropoietin critically regulates the terminal maturation of murine and human primitive erythroblastsHaematologica, 2013
- Functional NMDA receptors in rat erythrocytesAmerican Journal of Physiology-Cell Physiology, 2010
- Resolving the distinct stages in erythroid differentiation based on dynamic changes in membrane protein expression during erythropoiesisProceedings of the National Academy of Sciences of the United States of America, 2009
- Establishment of Mouse Embryonic Stem Cell-Derived Erythroid Progenitor Cell Lines Able to Produce Functional Red Blood CellsPLOS ONE, 2008
- Comparative analysis of structure, expression and PSD95-binding capacity of Lrfn, a novel family of neuronal transmembrane proteinsGene, 2006
- SALM Synaptic Cell Adhesion-like Molecules Regulate the Differentiation of Excitatory SynapsesNeuron, 2006
- A Novel Family of Adhesion-Like Molecules That Interacts with the NMDA ReceptorJournal of Neuroscience, 2006
- A rapid, simple, and humane method for submandibular bleeding of mice using a lancetLab Animal, 2005
- NMDA receptor–mediated regulation of human megakaryocytopoiesisBlood, 2003
- Ion channels in human erythroblasts. Modulation by erythropoietin.JCI Insight, 1992