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Review
. 2016 Jun;58(5):446-55.
doi: 10.1111/dgd.12297. Epub 2016 Jun 8.

GAP junctional communication in brain secondary organizers

Camilla Bosone  1 , Abraham Andreu  2 , Diego Echevarria  1
Affiliations
Review

GAP junctional communication in brain secondary organizers

Camilla Bosone et al. Dev Growth Differ. 2016 Jun.

Abstract

Gap junctions (GJs) are integral membrane proteins that enable the direct cytoplasmic exchange of ions and low molecular weight metabolites between adjacent cells. They are formed by the apposition of two connexons belonging to adjacent cells. Each connexon is formed by six proteins, named connexins (Cxs). Current evidence suggests that gap junctions play an important part in ensuring normal embryo development. Mutations in connexin genes have been linked to a variety of human diseases, although the precise role and the cell biological mechanisms of their action remain almost unknown. Among the big family of Cxs, several are expressed in nervous tissue but just a few are expressed in the anterior neural tube of vertebrates. Many efforts have been made to elucidate the molecular bases of Cxs cell biology and how they influence the morphogenetic signal activity produced by brain signaling centers. These centers, orchestrated by transcription factors and morphogenes determine the axial patterning of the mammalian brain during its specification and regionalization. The present review revisits the findings of GJ composed by Cx43 and Cx36 in neural tube patterning and discuss Cx43 putative enrollment in the control of Fgf8 signal activity coming from the well known secondary organizer, the isthmic organizer.

Keywords: Cx36; Cx43; Fgf8; gap junction; isthmic organizer; mammalian neural tube patterning; morphogenesis.

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Figures

Figure 1
Figure 1
Connexins structure and assembly into gap junctions (GJs). The sketch depicted in (a) show all the domains of a single connexin, the GJ monomer, as if it was ideally unraveled on a 2D plane in respect to the plasma membrane of a cell. Connexin protein feature four transmembrane hydrophobic domains (green), two extracellular domains (in purple), and three cytosolic domains: one conserved N‐terminal (in blue) and two variable cytoplasmic loops (CL) and tails (CT (in red). In this particular drawing, CT and CL are Cx43's ones, base on the hypothetical 3D model by (Sorgen et al. 2004). CT and CL are mainly random coil regions, hosting post‐translational modification consensus sites, so their structure in this picture is arbitral, for length comparison. (b) Same color code as (a) is used to show the relative position of a Cx43 domains assembled into a connexon (in yellow) in the typical hexameric conformation. Note that the extracellular domains dock the interactions with the juxtaposing connexon of the neighbor cell (in cyan), thus sealing the GJ. Note the position of the N‐terminal domains (NTs), facing the lumen of the junction (also in c). Gray arrow indicates the view plane of c. (c) orthogonal vision of an homomeric Cx43 GJ. All images were obtained with “Phyre2” homology modeling using “PDB database”, and elaborated with UCSF “Chimera” program.
Figure 2
Figure 2
Fgf8‐related Isthmic organizer players in mouse neurulation stage E8.0–8.5. (a–d) whole mount in situ hybridization for Fgf8 (a), Cx43 (b), Mkp3 (c) and whole mount immunohistochemistry for pERK (d). E represents the typical drawing of the morphogenetic activity of FGF8 protein arising from the isthmic organizer (IsO) in the rhombencephalon (Rh) that diffuses through the extracellular matrix and ventricle (vent), onto the mesencephalon (Mes) and diencephalon (Di) in a gradient manner. The pseudostratified neuroepithelial cells (NE) are inter‐connected and inter‐communicated by adherens junctions (AJ), tight junctions (TJ) and gap junctions (GJ‐Cx43). GJ made of Cx43 (in b) is distributed in a gradient along the NE as the protein FGF8, remembering also the expression pattern profile of Fgf8 downstream negative feedback modulator, Mkp3 (in c) and of Fgf8 intracellular MAP‐kinase product, the phosphorylated Extracellular signal‐Regulated Kinase 1/2 (pERK; in d).
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