Gap junction adhesion is necessary for radial migration in the neocortex

Neuroscience Graduate Program, University of California San Francisco, 513 Parnassus Avenue, San Francisco, California 94143, USA.
Nature (Impact Factor: 41.46). 09/2007; 448(7156):901-7. DOI: 10.1038/nature06063
Source: PubMed


Radial glia, the neuronal stem cells of the embryonic cerebral cortex, reside deep within the developing brain and extend radial fibres to the pial surface, along which embryonic neurons migrate to reach the cortical plate. Here we show that the gap junction subunits connexin 26 (Cx26) and connexin 43 (Cx43) are expressed at the contact points between radial fibres and migrating neurons, and acute downregulation of Cx26 or Cx43 impairs the migration of neurons to the cortical plate. Unexpectedly, gap junctions do not mediate neuronal migration by acting in the classical manner to provide an aqueous channel for cell-cell communication. Instead, gap junctions provide dynamic adhesive contacts that interact with the internal cytoskeleton to enable leading process stabilization along radial fibres as well as the subsequent translocation of the nucleus. These results indicate that gap junction adhesions are necessary for glial-guided neuronal migration, raising the possibility that the adhesive properties of gap junctions may have an important role in other physiological processes and diseases associated with gap junction function.

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Available from: Doris Wang, Dec 05, 2014
    • "firstly, radial glial cells in echinoderms are joined to their neighbours by apical zonulae adherentes and septate junctions (märkel andRöser 1991, mashanov et al. 2006), but no gap junctions have been identiied so far. likewise, although extensively searched for, no genes representing connexins or pannexins, two protein families known to form gap junctions, were found either in the sea urchin genome or in the sea cucumber transcriptome (Burke et al. 2006;mashanov et al., 2014). in mammals, gap junction formation in radial glia is required for embryonic and adult neurogenesis (Elias et al. 2007, Kunze et al. 2009). it remains to be elucidated whether echinoderms might have some unique gap junction proteins, unrelated to connexins and pannexins of other animals studied so far, or whether their radial glial cells can indeed perform their functions without having these intercellular coupling devices at all. "

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    • "Third, in addition to gap junctions mediating intercellular communication, they have been proposed to play a role in cell-cell adhesion (Elias et al., 2007; Falk et al., 2012) that may impact upon processes such as wound healing. For example, in wounded skin, up-regulation of Cx30 and Cx26 in all epidermal keratinocyte layers, and a concomitant decrease in Cx43 at the wound edge, are proposed to co-ordinate the keratinocyte wound healing response (Churko and Laird, 2013; Coutinho et al., 2003). "
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    ABSTRACT: In the present study we investigated the life-cycle, trafficking, assembly and cell surface dynamics of a poorly characterized connexin family member, connexin 30 (Cx30), which plays a critical role in skin health and hearing. Unexpectedly, Cx30 localization at the cell surface and gap junctional intercellular communication was not affected by prolonged treatments with the ER-Golgi transport inhibitor brefeldin-A or the protein synthesis inhibitor cycloheximide, whereas Cx43 was rapidly cleared. Fluorescent recovery after photobleaching revealed that Cx30 plaques were rebuilt from the outer edges in keeping with older channels residing in the inner core of the plaque. Expression of a dominant-negative form of Sar1 GTPase led to the accumulation of Cx30 within the ER in contrast to a report that Cx30 traffics via a Golgi-independent pathway. Co-expression of Cx30 with Cx43 revealed that these connexins segregate into distinct domains within common gap junction plaques suggesting their assembly is governed by different mechanisms. In summary, Cx30 was found to be an unusually stable, long-lived connexin (half-life >12 hrs), which may underlie its specific role in the epidermis and cochlea.
    Full-text · Article · Nov 2015 · Journal of Cell Science
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    • "Although there are still many open questions to understand the mechanism by which Cx43 controls proliferation, most of the studies pinpoint the C-terminal domain of Cx43 (Cx43CT) responsible for the antiproliferative effect (Moorby and Patel, 2001; Zhang et al., 2003b). As recently reviewed (Naus and Laird, 2010; Sin et al., 2012), this tumor suppressor effect could be counterbalanced by its effects on invasiveness (Zhang et al., 2003a), adhesion (Elias et al., 2007) and migration (Matsuuchi and Naus, 2013). Several interesting reviews about the link of connexins with cancer, including astrocytomas have appeared in recent years (Mesnil et al., 2005; Vinken et al., 2006; Naus and Laird, 2010; Sin et al., 2012). "
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    ABSTRACT: Connexin43 (Cx43) as a building block of gap junction channels and hemichannels exerts important functions in astrocytes. When these cells acquire a malignant phenotype Cx43 protein but not mRNA levels are downregulated, being negligible in high-grade astrocytoma or glioblastoma multiforme, the most common and deadliest of malignant primary brain tumours in adults. Some microRNAs associated to glioma target Cx43 and could explain the lack of correlation between mRNA and protein levels of Cx43 found in some high-grade astrocytomas. More importantly, these microRNAs could be a promising therapeutic target. A great number of studies have confirmed the relationship between cancer and connexins that was proposed by Loewenstein more than 40 years ago, but these studies have also revealed that this is a very complex relationship. Indeed, restoring Cx43 to glioma cells reduces their rate of proliferation and their tumorigenicity but this tumour suppressor effect could be counterbalanced by its effects on invasiveness, adhesion and migration. The mechanisms underlying these effects suggest the participation of a great variety of proteins that bind to different regions of Cx43. The present review focuses on an intrinsically disordered region of the C-terminal domain of Cx43 in which converges the interaction of several proteins, including the proto-oncogene Src. We summarize data that indicate that Cx43-Src interaction inhibits the oncogenic activity of Src and promotes a conformational change in the structure of Cx43 that allosterically modifies the binding to other important signalling proteins. As a consequence, crucial cell functions, such as proliferation or migration, could be strongly affected. We propose that the knowledge of the structural basis of the antitumorigenic effect of Cx43 on astrocytomas could help to design new therapies against this incurable disease. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Feb 2015 · Neuroscience
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