Publication Date:
2015-08-22
Description:
Resistance to inhibitors of cholinesterase 8A (Ric-8A) is a highly evolutionarily conserved cytosolic protein initially identified in Caenorhabditis elegans , where it was assigned a regulatory role in asymmetric cell divisions. It functions as a guanine nucleotide exchange factor for Gα i , Gα q , and Gα 12/13 and as a molecular chaperone required for the initial association of nascent Gα subunits with cellular membranes in embryonic stem cell lines. To test its role in hematopoiesis and B lymphocytes specifically, we generated ric8 fl/fl vav1-cre and ric8 fl/fl mb1 - cre mice. The major hematopoietic cell lineages developed in the ric8 fl/fl vav1-cre mice, notwithstanding severe reduction in Gα i2/3, Gα q , and Gα 13 proteins. B lymphocyte–specific loss of Ric-8A did not compromise bone marrow B lymphopoiesis, but splenic marginal zone B cell development failed, and B cells underpopulated lymphoid organs. The ric8 fl/fl mb1 - cre B cells exhibited poor responses to chemokines, abnormal trafficking, improper in situ positioning, and loss of polarity components during B cell differentiation. The ric8 fl/fl mb1 - cre mice had a severely disrupted lymphoid architecture and poor primary and secondary Ab responses. In B lymphocytes, Ric-8A is essential for normal Gα protein levels and is required for B cell differentiation, trafficking, and Ab responses.
Print ISSN:
0022-1767
Electronic ISSN:
1550-6606
Topics:
Medicine
Permalink
