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Pozzi, B.* ; Amodio, S.* ; Lucano, C.* ; Sciullo, A.* ; Ronzoni, S.* ; Castelletti, D.* ; Adler, T. ; Treise, I. ; Holmberg-Betsholtz, I.* ; Rathkolb, B. ; Busch, D.H.* ; Wolf, E.* ; Fuchs, H. ; Gailus-Durner, V. ; Hrabě de Angelis, M. ; Betsholtz, C.* ; Casola, S.* ; di Fiore, P.P.* ; Offenhäuser, N.*

The endocytic adaptor Eps15 controls marginal zone B cell numbers.

PLoS ONE 7:e50818 (2012)

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Eps15 is an endocytic adaptor protein involved in clathrin and non-clathrin mediated endocytosis. In Caenorhabditis elegans and Drosophila melanogaster lack of Eps15 leads to defects in synaptic vesicle recycling and synapse formation. We generated Eps15-KO mice to investigate its function in mammals. Eps15-KO mice are born at the expected Mendelian ratio and are fertile. Using a large-scale phenotype screen covering more than 300 parameters correlated to human disease, we found that Eps15-KO mice did not show any sign of disease or neural deficits. Instead, altered blood parameters pointed to an immunological defect. By competitive bone marrow transplantation we demonstrated that Eps15-KO hematopoietic precursor cells were more efficient than the WT counterparts in repopulating B220(+) bone marrow cells, CD19(-) thymocytes and splenic marginal zone (MZ) B cells. Eps15-KO mice showed a 2-fold increase in MZ B cell numbers when compared with controls. Using reverse bone marrow transplantation, we found that Eps15 regulates MZ B cell numbers in a cell autonomous manner. FACS analysis showed that although MZ B cells were increased in Eps15-KO mice, transitional and pre-MZ B cell numbers were unaffected. The increase in MZ B cell numbers in Eps15 KO mice was not dependent on altered BCR signaling or Notch activity. In conclusion, in mammals, the endocytic adaptor protein Eps15 is a regulator of B-cell lymphopoiesis.

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