Abstract
Neurexin I α (NRXN1α) and Dystroglycan (DAG1) are membrane receptors which serve as mutual ligands in the neuronal system. Neurexophilins (NXPHs) bind NRXN1α. NRXN1α was expressed in primitive populations in human CB (huCB) and murine BM (muBM). DAG1 is ubiquitously expressed in hematopoietic tissue; however, osteoblasts appear to be sites of very high expression within muBM. High concentrations of NXPH were found in huCB plasma and murine lineage-positive splenocytes. We evaluated effects of these molecules on huCB and muBM hematopoietic progenitor cells (HPCs) and HSCs. At both a single and population cell level in vitro, we found that NXPH1 was a potent inhibitor of HPC proliferation acting through NRXN1α an effect down-modulated by DAG1. Injection of recombinant NXPH1 in vivo resulted in myelo- and lymphosuppression in the BM, with absolute numbers and cycling status of functional and phenotypically defined HPCs dose- and time-dependently decreased. Competitive HSC transplantations showed no change in the long-term repopulating activity of HSCs from mice exposed to recombinant NXPH1. These results demonstrate the presence and function of a regulated signaling axis in hematopoiesis centered on NRXN1α and its modulation by DAG1 and NXPH1.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Bone Marrow Cells / cytology
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Bone Marrow Cells / physiology
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Calcium-Binding Proteins
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Cell Adhesion Molecules, Neuronal / genetics
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Cell Adhesion Molecules, Neuronal / metabolism
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Cell Division / physiology
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Cells, Cultured
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Dystroglycans / metabolism
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Flow Cytometry
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Glycoproteins / genetics*
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Glycoproteins / metabolism*
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Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
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Hematopoiesis / physiology
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Hematopoietic Stem Cells / cytology*
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Hematopoietic Stem Cells / physiology*
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Humans
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Mice
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Mice, Inbred C57BL
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Neural Cell Adhesion Molecules / genetics
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Neural Cell Adhesion Molecules / metabolism
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Neuropeptides / genetics*
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Neuropeptides / metabolism*
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Osteoblasts / cytology
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Osteoblasts / physiology
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Signal Transduction / physiology
Substances
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Calcium-Binding Proteins
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Cell Adhesion Molecules, Neuronal
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DAG1 protein, human
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Glycoproteins
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NRXN1 protein, human
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Nerve Tissue Proteins
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Neural Cell Adhesion Molecules
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Neuropeptides
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Nrxn1 protein, mouse
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Recombinant Proteins
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neurexophilin
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Dystroglycans
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Granulocyte-Macrophage Colony-Stimulating Factor