Spatiotemporal Regulation of Rho GTPases in Neuronal Migration

Abstract

Neuronal migration is essential for the orchestration of brain development and involves several contiguous steps: interkinetic nuclear movement (INM), multipolar-bipolar transition, locomotion, and translocation. Growing evidence suggests that Rho GTPases, including RhoA, Rac, Cdc42, and the atypical Rnd members, play critical roles in neuronal migration by regulating both actin and microtubule cytoskeletal components. This review focuses on the spatiotemporal-specific regulation of Rho GTPases as well as their regulators and effectors in distinct steps during the neuronal migration process. Their roles in bridging extracellular signals and cytoskeletal dynamics to provide optimal structural support to the migrating neurons will also be discussed.

Keywords: GTPase-activating protein; Rho GTPase; guanine nucleotide exchange factor; neuronal development; neuronal migration.

Figure 1

Rho GTPases regulate neurogenesis or interkinetic nuclear migration (INM). (A) Radial glial progenitors (RGPs) line the ventricular surface and exhibit apical–basal polarity. The nuclei within RGPs undergo an oscillatory form of cycle-dependent migration, which leads to symmetric or asymmetric cell division at the ventricular surface; the former expands the RGP pool, and the latter generates basal progenitors or neurons. Rac1 and Rnd3 promote basal–apical migration. (B) The proper structure of RGPs depends on the maintenance of adherens junctions and cell polarity, which are regulated by Cdc42 and RhoA. Adherens junctions directly link adjacent RGPs via junctional complex, which is a quaternary complex comprising cadherin, β-catenin, α-catenin, and actin filaments. Both Cdc42 and RhoA may help tension the link between α-catenin and actin filaments. In addition, Cdc42 contributes to maintaining cell polarity through Par6/aPKC/Par3 complex. (C) Besides cell structure, Cdc42 and RhoA help balance the proliferation and differentiation of RGPs. RhoA primarily regulates mitotic spindle orientation and cytokinesis through Aurora kinase B (Aurkb). Cdc42 mainly promotes self-renewing ability through regulating the apical localization of Numb and Par6/aPKC/Par3 complex.

Figure 2

Rho GTPases regulate the multipolar–bipolar transition of nascent neurons. (A) There are two differentiation modes by which RGPs become multipolar neurons, which are represented by two populations: the “rapidly exiting population” (REP, green) and the “slowly exiting population” (SEP, red). In the REP route, RGPs generate intermediate progenitors (IPs), which undergo division and differentiate into neurons. In the SEP route, RGPs directly produce nascent neurons that remain in the lower part of the subventricular zone (SVZ). Both SEP and REP neurons acquire a multipolar morphology in lower intermediate zone (IZ) and take on a bipolar morphology when they reach the cortical plate (CP). (B) The multipolar–bipolar transition relies on actin and microtubule dynamics, which are under the precise regulation of various promotive factors (purple) and inhibitory factors (blue). Globally, the Rac1 pathway is activated to promote both actin and microtubule dynamics, while RhoA activity is inhibited by several factors. The functions of Cdc42 are still unclear.

Figure 3

Rho GTPases regulate locomotion and terminal translocation. (A) Neurons migrate radially along RGPs until they reach the marginal zone and receive a stop signal to uncouple from RGPs at their final destinations. (B) In the locomotion process, leading process and dilation formation rely on the proper distribution of activated Rac1. Rac1 regulates both actin (red) and microtubule (green) dynamics through distinct pathways. In addition, RhoA activity should be inhibited during locomotion; Rnd3 is a key inhibitory factor of RhoA. Pulling force is generated by three contractile centers under the regulation of Cdc42 and RhoA. Cdc42 mainly functions in the two contractile centers localized at the distal and proximal regions of the leading process, while RhoA contributes to retraction of the trailing process. Most factors (red) regulate actin dynamics through non-muscle myosin-II, while some factors (blue) help tie microtubule ends with the actin cytoskeleton. (C) RhoA transduces stop signals to migrating neurons in terminal translocation. Upon interacting with collagen III, RGP56 couples to Gα12/13 and thus activates the RhoA pathway.