RalA promotes a direct exocyst-Par6 interaction to regulate polarity in neuronal development

Abstract

Cell polarization is essential for neuronal development in both the embryonic and postnatal brain. Here, using primary cultures, in vivo postnatal electroporation and conditional genetic ablation, we show that the Ras-like small GTPase RalA and its effector, the exocyst, regulate the morphology and polarized migration of neural progenitors derived from the subventricular zone, a major neurogenic niche in the postnatal brain. Active RalA promotes the direct binding between the exocyst subunit Exo84 and the PDZ domain of Par6 through a non-canonical PDZ-binding motif. Blocking the Exo84-Par6 interaction impairs polarization in postnatal neural progenitors and cultured embryonic neurons. Our results provide the first in vivo characterization of RalA function in the mammalian brain and highlight a novel molecular mechanism for cell polarization. Given that the exocyst and the Par complex are conserved in many tissues, the functional significance of their interaction and its regulation by RalA are likely to be important in a wide range of polarization events.

The Exocyst at a Glance

“…Studies have also shown that the exocyst functions together with Rab8 and the Par3/6 complex in membrane trafficking to the apical domain (Blankenship et al, 2007;Oztan et al, 2007;Bryant et al, 2010). In neurons, the exocyst is localized to the growth cones, tips of neurites or points of branching, where exocytosis is needed for membrane addition and surface expansion (Hazuka et al, 1999;Vega and Hsu, 2001;Lalli and Hall, 2005;Das et al, 2014). Inhibition of the exocyst does not affect neural transmitter release at mature synapses (Andrews et al, 2002;EauClaire and Guo, 2003;Murthy et al, 2003).…”

“…The exocyst was also reported to interact with the endosomal Wiskott-Aldrich syndrome protein and Scar homolog (WASH) complex, thus coupling generation of membrane Type-1 MMP-containing late endosomes to their exocytosis at the plasma membrane (Monteiro et al, 2013). In neurons, the exocyst interacts with the Par3/6 complex under the control of Ral to regulate polarized neuronal cell migration (Lalli, 2009;Das et al, 2014).…”

“…Rab10 also interacts with the exocyst and mediate ciliogenesis in renal epithelial cells, probably through a similar mechanism (Babbey et al, 2010). The interaction of exocyst with the Par3/6 complex might also contribute to primary ciliogenesis, although direct evidence for this notion is lacking (Zuo et al, 2009;Lalli, 2009;Das et al, 2014).…”

The RAS-RAL axis in cancer: evidence for mutation-specific selectivity in non-small cell lung cancer

“…On the other hand, the RALA/Exo84 complex is known to regulate the morphology and polarized migration of neuronal progenitor cells. Loss of the RALA/Exo84 interaction hampers polarity in postnatal migratory neuroblasts and embryonic neurons [47] . Thus, RALA/Exo84 can promote cellular migration by altering cell polarization [47] .…”

Alterações transcriptômicas no hipocampo de ratos submetidos a um modelo experimental de epilepsia com insulto precipitante febril

“…Por exemplo, o hub RaiA (Ras-like small GTPase) está envolvido na polarização celular durante o desenvolvimento neuronal (DAS et al, 2014).…”