Connexins and pannexins in neuronal development and adult neurogenesis

Abstract

Connexins and pannexins share very similar structures and functions; they also exhibit overlapping expression in many stages of neuronal development. Here, we review evidence implicating connexin- and pannexin-mediated communication in the regulation of the birth and development of neurons, specifically Cx26, Cx30, Cx32, Cx36, Cx43, Cx45, Panx1, and Panx2. We begin by dissecting the involvement of these proteins in the generation and development of new neurons in the embryonic, postnatal, and adult brain. Next we briefly outline common mechanisms employed by both pannexins and connexins in these roles, including modulation of purinergic receptor signalling and signalling nexus functions. Throughout this review we highlight developing themes as well as important gaps in knowledge to be bridged.

Fig. 1

Cx and Panx nexuses. a Cxs are the structural units of single membrane channels (hemichannels) and intercellular channels (gap junctions). Panxs are primarily single-membrane channel proteins. Membrane topology in monomeric form (i.e., Panx1, blue) is strikingly similar to that of a connexin (i.e., Cx43, red). b Panxs exclusively form single-membrane pores composed of Panx1 hexamers, Panx2 octomers, or possibly Panx1/2 heterotypic channels of unknown numbers of protein subunits. c Cxs oligomerize to hexamers capable of forming single membrane channels (homotypic connexons or hemichannels are indicated). Schematic models crystal structure in a non-junctional lipid bilayer. d Axial alignment of compatible Cx connexons generate homotypic (blue connexon/blue connexon), heterotypic (yellow connexon/blue connexon), and heteromeric (blue-yellow connexon/blue-yellow connexon). e Cx26, Cx30, and Cx43 are expressed by astrocytes. Cx29, Cx32, and Cx47 are expressed by oligodendrocytes. Cx32 is expressed by oligodendrocyte precursor cells (OPCs). Cx36 and Cx45 are expressed by neurons. Cx45 and Cx30 are expressed by NPCs. Panx1 is expressed by astrocytes, OPCs, oligodendrocytes, and neurons. Panx2 is found in neurons and NPCs. Panx single membrane channels, Cx hemichannels/connexons, and Cx-compatible gap junction channels are depicted. Abbreviations: CT, carboxyl termini domain; E1/E2, extracellular loop domains; IL, intracellular loop; JXP, juxtaparanode; M1-M4, transmembrane domains; NT, amino termini domain. Representations are based on [–127]

Fig. 2

The adult SVZ and SGZ support neurogenesis. Adult NPCs are defined by their capacity to proliferate and replenish neuronal and glial numbers. Antigenic markers used to distinguish between lineages are listed

Fig. 3

Connexon-Connexon mediated adhesion domains. In addition to forming functional intercellular channels, docking of compatible connexons between radial glia (yellow) and NPCs (gold) directs migration of NPCs Docking and undocking enables the “rolling” of NPCs along their radial glial guides to their final location before terminal differentiation. Adhesion can be channel-independent without requiring exchange of small molecules or functional channel opening