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
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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.
    Journal of Cell Science 11/2015; 128:3947-3960. DOI:10.1242/jcs.174698 · 5.43 Impact Factor
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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.
    Neuroscience 02/2015; DOI:10.1016/j.neuroscience.2015.02.029 · 3.36 Impact Factor
    • "Beneath the cortical plate, postmitotic neurons transform into unipolar-shaped cells and attach to the radial glial fibers to rapidly migrate along it until near the pial surface (Rakic, 1972; Nadarajah et al., 2001). Although hemichannels formed of connexin 26 and connexin 43 are shown to be necessary for radial glial-guided neuronal migration in the neocortex (Elias et al., 2007), pharmacological inhibition of the P2Y 1 receptor with suramin or shRNA knockdown had no affect on the migration process. These results suggest that Ca 21 waves mediated by connexin-hemichannels are the not the main player in neuronal migration. "
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    ABSTRACT: The calcium ion (Ca(2+) ) is an essential second messenger that plays a pivotal role in neurogenesis. In the ventricular zone of the neocortex, neural stem cells linger to produce progenitor cells and subsequently neurons and glial cells, which together build up the entire adult brain. The radial glial cells, with their characteristic radial fibers that stretch from the inner ventricular wall to the outer cortex, are known to be the neural stem cells of the neocortex. Migrating neurons use these radial fibers to climb from the proliferative ventricular zone in the inner part of the brain to the outer layers of the cortex, where differentiation processes continue. To establish the complex structures that constitute the adult cerebral cortex, proliferation, migration, and differentiation must be tightly controlled by various signaling events, including cytosolic Ca(2+) signaling. During development, cells regularly exhibit spontaneous Ca(2+) activity that stimulates downstream effectors, which can elicit these fundamental cell processes. Spontaneous Ca(2+) activity during early neocortical development depends heavily on gap junctions and voltage dependent Ca(2+) channels, whereas later in development neurotransmitters and synapses exert an influence. Here, we provide an overview of the literature on Ca(2+) signaling and its impact on cell proliferation, migration, and differentiation in the neocortex. We point out important historical studies and review recent progress in determining the role of Ca(2+) signaling in neocortical development. This article is protected by copyright. All rights reserved. Copyright © 2015 Wiley Periodicals, Inc., a Wiley company.
    Developmental Neurobiology 02/2015; 75(4). DOI:10.1002/dneu.22273 · 3.37 Impact Factor
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