Ephrin B1 maintains apical adhesion of neural progenitors

Abstract

SUMMARYApical neural progenitors are polarized cells for which the apical membrane is the site of cell-cell and cell-extracellular matrix adhesion events that are essential for maintaining the integrity of the developing neuroepithelium. Apical adhesion is important for several aspects of the nervous system development, including morphogenesis and neurogenesis, yet the mechanisms underlying its regulation remain poorly understood. Here, we show that ephrin B1, a cell surface protein that engages in cell signaling upon binding cognate Eph receptors, controls normal morphogenesis of the developing cortex. Efnb1-deficient embryos exhibit morphological alterations of the neuroepithelium that correlate with neural tube closure defects. Using loss-of-function experiments by ex vivo electroporation, we demonstrate that ephrin B1 is required in apical progenitors (APs) to maintain their apical adhesion. Mechanistically, we show that ephrin B1 controls cell-ECM adhesion by promoting apical localization of integrin β1 and we identify ADP-ribosylation factor 6 (Arf6) as an important effector of ephrin B1 reverse signaling in apical adhesion of APs. Our results provide evidence for an important role for ephrin B1 in maintaining the structural integrity of the developing cortex and highlight the importance of tightly controlling apical cell-ECM adhesion for neuroepithelial development.

TBC1D24 regulates neuronal migration and maturation through modulation of the ARF6-dependent pathway

“…These observations suggest that TBC1D24 regulates radial neuronal migration by maintaining ARF6 in the inactive GDP-bound state. In fact, a recent report showed that low ARF6-GTP levels are also necessary in the early stages of corticogenesis to maintain the apical localization of integrin β1 receptor in neuronal progenitors, a process crucial for apical adhesion and, therefore, for neuroepithelium integrity (15). Furthermore, the combination of TBC1D24 knockdown and overexpression of the constitutively active form of ARF6 displayed no synergistic effect on neuronal migration, leading us to hypothesize that TBC1D24 may act upstream to ARF6 pathway to control the turnover of adhesion molecules and/or the remodeling of the cytoskeleton.…”

“…The TBC1D24 protein is expressed in the brain and interacts with the ADP ribosylation factor (ARF) 6, a small GTP-binding protein implicated in membrane exchange between the plasma membrane and the endocytic compartments (8,12). In the brain, ARF6 is known to play various roles including regulation of neurite outgrowth (13,14) and maintenance of apical adhesion of neural progenitors in the developing neocortex (15). Interestingly, pathogenic mutations in TBC1D24 affect its binding to ARF6 and result in a severe impairment of neuronal development (7,8,10).…”

Altered proliferative ability of neuronal progenitors in PlexinA1 mutant mice

“…Thus, it is possible that PlexinA1 could be acting as an integrin coreceptor required for laminin binding and attachment to the ECM. Interestingly, ephrin B1 signaling has been shown to enhance ECM adhesion of neuroepithelial cells by promoting apical localization of integrin β1 (Arvanitis et al, 2013). By analogy, loss of PlexinA1 function might impair the apical distribution of integrins in progenitor cells and, thereby, affect their ability to attach properly to the ECM and consequently impair their capacity to divide.…”

Tuning Collective Cell Migration by Cell–Cell Junction Regulation

“…Phosphorylation of the intracellular domains of Ephs regulates the recruitment of effector proteins, such as the noncatalytic regions of Tyr kinase adaptor protein 1 (Nck1) and Nck2, Vav2 and Vav3, Src, a2-chimerin, and ephexins, which directly regulate actin or modulate the activity of the small GTPases RhoA and Rac1 (Kania and Klein 2016). Normal morphogenesis of the neural tube and neural progenitors requires ephrin-dependent cellcell adhesion (Arvanitis et al 2013), and alternative usage of different splice forms of Eph receptor was implicated in mediating cell-cell coupling during embryonic development. Eph signaling promotes the formation of AJ through interaction with E-cadherin and TJs via the interaction with claudin (Dravis and Henkemeyer 2011).…”