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

ABSTRACT 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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    • "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
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    • "However, the exclusive use of such animals does not distinguish between the contributions of the two types of astroglial Cxs as well as between the channel and hemichannel functions that they support (Giaume and Theis, 2010). So far, the use of single Cx knock-out mice has provided key data demonstrating a role of Cx43 in neuronal migration (Elias et al., 2007; Cina et al., 2009), a synaptic activitydependent modulation of Cx30 gap junctions in astrocytes in the olfactory bulb (Roux et al., 2011) and recently, it was reported that the lack of Cx30 impacts synaptic transmission through the modulation of astroglial glutamate transport (Pannasch et al., 2014). However, there is still a need to develop new pharmacological tools to design in vitro and in vivo experiments studying the role of Cxs in astrocytes. "
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    ABSTRACT: In the brain, astrocytes represent the cellular population that expresses the highest amount of connexins (Cxs). This family of membrane proteins is the molecular constituent of gap junction channels and hemichannels that provide pathways for direct cytoplasm-to-cytoplasm and inside-out exchange, respectively. Both types of Cx channels are permeable to ions and small signaling molecules allowing astrocytes to establish dynamic interactions with neurons. So far, most pharmacological approaches currently available do not distinguish between these two channel functions, stressing the need to develop new specific molecular tools. In astrocytes two major Cxs are expressed, Cx43 and Cx30, and there is now evidence indicating that at least Cx43 operates as a gap junction channel as well as a hemichannel in these cells. Based on studies in primary cultures as well as in acute hippocampal slices, we report here that Gap19, a nonapeptide derived from the cytoplasmic loop of Cx43, inhibits astroglial Cx43 hemichannels in a dose-dependent manner, without affecting gap junction channels. This peptide, which not only selectively inhibits hemichannels but is also specific for Cx43, can be delivered in vivo in mice as TAT-Gap19, and displays penetration into the brain parenchyma. As a result, Gap19 combined with other tools opens up new avenues to decipher the role of Cx43 hemichannels in interactions between astrocytes and neurons in physiological as well as pathological situations.
    Frontiers in Cellular Neuroscience 10/2014; 8:306. DOI:10.3389/fncel.2014.00306 · 4.29 Impact Factor
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    • "A number of studies specifically examining the role of connexin 43 gap junctions/hemi channels in NPSCs have demonstrated a critical role for this protein during NPSC proliferation and differentiation (Cheng et al., 2004; Elias et al., 2007; Samarasinghe et al., 2011; Weissman et al., 2004). A provocative study by Elias et al., demonstrated a non-traditional role for Cx43 in neurodevelopment wherein the protein behaved as an essential anchor for radial glial cell migration (Elias et al., 2007). Interestingly, cortical dysplasia has been noted in surgical specimens from refractory TLE as well as in focal cortical dysplasia (FCD) type epileptic brains (Garbelli et al., 2011; Kuzniecky et al., 1991). "
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    ABSTRACT: While aberrant cell proliferation and differentiation may contribute to epileptogenesis, the mechanisms linking an initial epileptic insult to subsequent changes in cell fate remain elusive. Using both mouse and human iPSC-derived neural progenitor/stem cells (NPSCs), we found that a combined transient muscarinic and mGluR1 stimulation inhibited overall neurogenesis but enhanced NPSC differentiation into immature GABAergic cells. If treated NPSCs were further passaged, they retained a nearly identical phenotype upon differentiation. A similar profusion of immature GABAergic cells was seen in rats with pilocarpine-induced chronic epilepsy. Furthermore, live cell imaging revealed abnormal de-synchrony of Ca(++) transients and altered gap junction intercellular communication following combined muscarinic/glutamatergic stimulation, which was associated with either acute site-specific dephosphorylation of connexin 43 or a long-term enhancement of its degradation. Therefore, epileptogenic stimuli can trigger acute and persistent changes in cell fate by altering distinct mechanisms that function to maintain appropriate intercellular communication between coupled NPSCs.
    Neurobiology of Disease 07/2014; 70. DOI:10.1016/j.nbd.2014.06.020 · 5.08 Impact Factor
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