Dysregulation of erythropoiesis and altered erythroblastic NMDA receptor-mediated calcium influx in Lrfn2-deficient mice

• Published in: PloS one Vol. 16; no. 1; p. e0245624
• Main Authors: Maekawa, Ryuta, Muto, Hideki, Hatayama, Minoru, Aruga, Jun
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 22-01-2021; Public Library of Science (PLoS)
• Subjects: Adhesion; Animals; Antibodies; Biology and Life Sciences; Blood tests; Bone growth; Bone marrow; Calcium; Calcium - metabolism; Calcium chloride; Calcium influx; Calcium Signaling; Cell adhesion; Cell adhesion & migration; Cell adhesion molecules; Cell culture; Cell receptors; Cell suspensions; Colonies; Dizocilpine; Erythroblasts - metabolism; Erythrocytes; Erythropoiesis; Flow cytometry; Function analysis; Genetic aspects; Glucose; Glutamic acid receptors (ionotropic); Health aspects; Hematopoiesis; Hemopoiesis; Leukocytes (granulocytic); Macrophages; Male; Medical research; Membrane Glycoproteins - deficiency; Membrane Glycoproteins - metabolism; Methyl aspartate; Mice; Mice, Knockout; N-Methyl-D-aspartic acid receptors; Nerve Tissue Proteins - deficiency; Nerve Tissue Proteins - metabolism; Neural stem cells; Pharmacology; Physiological aspects; Potassium chloride; Proteins; Receptors; Receptors, N-Methyl-D-Aspartate - genetics; Receptors, N-Methyl-D-Aspartate - metabolism; Research and Analysis Methods; Sodium chloride; Spleen; Synaptogenesis; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0245624

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.