Connexin-mediated regulation of gliogenesis

Abstract

Connexin (Cx) proteins are important in coordinating neural progenitor cell behaviour. Here, we show hippocampal-derived neural progenitor cells (NPCs) express a wide and novel repertoire of Cxs when cultured in vitro. This repertoire can be modulated by exposure to the extracellular matrix component laminin which translates into functional changes in Cx-mediated signaling within hippocampal NPCs and their progeny. Novel localization of Cx29 to NPC-derived oligodendrocyte progenitor cells (OPCs) in these cultures prompted us to investigate what role Cx29 may have in maintenance, proliferation and specification of OPCs to oligodendrocytes in the hippocampus. Using a loss-of-function approach, we show loss of Cx29 results in reduced OPC and oligodendrocyte numbers with a concomitant increase in astrocyte number. However, investigation of Cx29 in vivo, which also shows localization to OPCs and oligodendrocytes, reveals the role of Cx29 in oligodendrocyte specification may be overridden by the additional cues present in the microenvironment as an increase in NG2+ OPC proliferation is observed. However, the effect on astrocyte proliferation is likely cell intrinsic because increased astrocyte proliferation is maintained in vivo. Closer examination of the hippocampal OPC population further indicates Cx32 but not Cx47 is expressed by subsets of OPCs while Cx47 is restricted to mature oligodendrocytes. Similar to the loss of Cx29, the loss of Cx32 in vivo results in increased proliferation of NG2 + OPCs. These data can be reconciled by the novel finding that Cx29 and Cx32 likely have complementary roles in the regulation of OPC proliferation and specification and can mutually compensate for the loss of the other connexin in the OPC subpopulations of null-mutant mice. Modulation of these Cxs may thus result in new therapeutic approaches to the treatment of diseases where oligodendrocytes are primarily affected such as multiple sclerosis and where augmenting progenitor cell specification is a viable treatment option.