Expression of connexin 43 (Cx43) is critical for normal hematopoiesis

Gap junctions are intercellular channels, formed by individual structural units known as connexins (Cx), that allow the intercellular exchange of various messenger molecules. The finding that numbers of Cx43-type gap junctions in bone marrow are elevated during establishment and regeneration of the hematopoietic system has led to the hypothesis that expression of Cx43 is critical during the initiation of blood cell formation. To test this hypothesis, lymphoid and myeloid development were examined in mice with a targeted disruption of the gene encoding Cx43. Because Cx43-/- mice die perinatally, initial analyses were performed on Cx43-/-, Cx43+/-, and Cx43+/+ embryos and newborns. The data indicate that lack of Cx43 expression during embryogenesis compromises the terminal stages of primary T and B lymphopoiesis. Cx43-/- embryos and neonates had a reduced frequency of CD4(+) and T-cell receptor-expressing thymocytes and surface IgM(+) cells compared to their Cx43+/+ littermates. Surprisingly, Cx43+/- embryos/neonates also showed defects in B- and T-cell development similar to those observed in Cx43-/- littermates, but their hematopoietic system was normal at 4 weeks of age. However, the regeneration of lymphoid and myeloid cells was severely impaired in the Cx43+/- mice after cytoablative treatment. Taken together, these data indicate that loss of a single Cx43 allele can affect blood cell formation. Finally, the results of reciprocal bone marrow transplants between Cx43+/+ and Cx43+/- mice and examination of hematopoietic progenitors and stromal cells in vitro indicates that the primary effects of Cx43 are mediated through its expression in the hematopoietic microenvironment.