Connexin 43 controls the multipolar phase of neuronal migration to the cerebral cortex

Abstract

The prospective pyramidal neurons, migrating from the proliferative ventricular zone to the overlaying cortical plate, assume multipolar morphology while passing through the transient subventricular zone. Here, we show that this morphogenetic transformation, from the bipolar to the mutipolar and then back to bipolar again, is associated with expression of connexin 43 (Cx43) and, that knockdown of Cx43 retards, whereas its overexpression enhances, this morphogenetic process. In addition, we have observed that knockdown of Cx43 reduces expression of p27, whereas overexpression of p27 rescues the effect of Cx43 knockdown in the multipolar neurons. Furthermore, functional gap junction/ hemichannel domain, and the C-terminal domain of Cx43, independently enhance the expression of p27 and promote the morphological transformation and migration of the multipolar neurons in the SVZ/IZ. Collectively, these results indicate that Cx43 regulates the passage of migrating neurons through their multipolar stage via p27 signaling and that interference with this process, by either genetic and/or environmental factors, may cause cortical malformations.T he laminated structure of the mammalian cerebral cortex is an end product of coordinated generation, migration, and deposition of neurons to their final locations during the embryonic period (1). All prospective cortical pyramidal neurons are generated in either the ventricular (VZ) or subventricular (SVZ) zones and, after their final division, migrate radially to the cortical plate (CP) situated beneath the pial surface (2). Although it has been observed long ago that cells in the SVZ and intermediate zone (IZ) display multiple processes as they choose and translocate between adjacent radial glial fibers (3, 4), it has been only until recently possible to study this transient process by live imaging combined with genetic introduction of GFP (5-9). The newly generated neurons usually undergo transient multipolar transformation before assuming radial migration (8, 10). Based on these observations, it has been proposed that many developmental disorders, such as periventricular nodular heterotopia, subcortical band heterotopia, and doublecortex syndrome are related to migration abnormalities including its multipolar stage at SVZ/VZ (11-13).The molecular mechanisms controlling directly and/or indirectly the multipolar stage of neuronal migration have just begun to be recognized (7,(14)(15)(16)(17). For example, knockdown or inactivation of Filamin A or LIS1 accumulated the multipolar neurons in the VZ and SVZ, whereas knockdown or inactivation of Doublecortin (DCX) accumulated these cells in the IZ (18,19). Conversely, increasing filamin A activity by siRNA of Filamin A-interacting protein accelerated the transition to a bipolar shape in the SVZ, and overexpression of DCX increased the number of bipolar cells in the IZ (20,21). In addition, Cdk5 has also been shown to control the multipolar-to-bipolar transition during radial migration (7,18,20). Recently, it has been reported that t...

Connexin hemichannels contribute to spontaneous electrical activity in the human fetal cortex

“…5A and Fig. S3), consistent with an idea that Cx43 plays an important role in tangential migration and maturation of GABAergic neurons, as it does in radial migration of glutamatergic cells (45,46).…”

“…Gap junctions and hemichannels have been broadly implicated in the control of embryonic patterning of the neocortex, including neuronal proliferation, maturation, and differentiation (45,46). Gap junctions contribute to the generation of cortical circuits by mediating oscillatory patterns of electrical activity in the neonatal mouse cerebral cortex (7,22,47) and are an important means of intracellular communication at this age (46,48 5A).…”

Neural progenitors organize in small-world networks to promote cell proliferation

“…Cx43 is a major gap junction channel that has been implicated in neural development of the embryonic brain (29,(31)(32)(33)(34). Expression of Cx43 in ES cell-derived neural progenitors expressing nestin was confirmed with immunocytochemistry ( Fig.…”

External Dentin Stimulation Induces ATP Release in Human Teeth

“…Inotropic purinergic P2X3 receptors are expressed in dental pulpal nerve fibers (Alavi et al 2001), which supports a role for ATP signaling in mediating dentin hypersensitivity and dental pain (Magloire et al 2010). Previous work found that odontoblasts express the gap junction/hemichannel protein connexin 43, which mediates ATP release upon intracellular and extracellular stimulation with 0mM Ca , and NO signals (Retamal et al 2009;Liu et al 2010;Nakagawa et al 2010;Liu, Sun, et al 2012). Therefore, ATP released from odontoblasts could then activate nearby P2X3 receptors on dental pulp nerve fibers to depolarize the membrane potential and initiate the nociception signals for dentin hypersensitivity.…”