The role of Rho GTPase proteins in CNS neuronal migration

Abstract

The architectonics of the mammalian brain arise from a remarkable range of directed cell migrations, which orchestrate the emergence of cortical neuronal layers and pattern brain circuitry. At different stages of cortical histogenesis, specific modes of cell motility are essential to the stepwise formation of cortical architecture. These movements range from interkinetic nuclear movements in the ventricular zone, to migrations of early-born, postmitotic polymorphic cells into the preplate, to the radial migration of precursors of cortical output neurons across the thickening cortical wall, and the vast, tangential migrations of interneurons from the basal forebrain into the emerging cortical layers. In all cases, actomyosin motors act in concert with cell adhesion receptor systems to provide the force and traction needed for forward movement. As key regulators of actin and microtubule cytoskeletons, cell polarity, and adhesion, the Rho GTPases play critical roles in CNS neuronal migration. This review will focus on the different types of migration in the developing neocortex and cerebellar cortex, and the role of the Rho GTPases, their regulators and effectors in these CNS migrations, with particular emphasis on their involvement in radial migration.

Figure 1

Modes of Cell Migration in the Developing CNS. Fibroblast (top cell) locomotion and and growth cone extension during neurite outgrowth (second cell) occurs by a general model of motility that involves the formation of an actin-rich lamellipodial protrusion at the leading edge in the front of the cell. Tangentially migrating CNS neurons (third cell) extend a leading process and form a swelling that contains the centrosome and Golgi, which moves into the leading process, followed by nuclear translocation. Glial-guided neuronal migration (fourth cell) involves the extension of a leading process, acto-myosin contractility in the proximal portion of the leading process, and forward movement of the centrosome prior to the nucleus. Red zones, actin; green, microtubules; orange circles, vesicles; purple circles, centrosome.

Figure 2

Scanning Electron Microscopy of Neural Progenitors in the Cerebral Vesicle. After neural tube closure (E9.25), the neuroepithelium along the third ventricle contains interphase progenitor cells that extend from the outer pial surface (P) to the inner ventricular surface (V), and mitotic cells are located closer to the ventricular surface. The movement of the nucleus from the ventricular surface to the pial surface and back again, during the cell cycle, is called interkinetic migration. (Inset) A low-power view of the hamster cerebral vesicle, corresponding roughly to that of a human embryo at the end of the first month of gestation. From Sidman and Rakic (1973).

Figure 3

Embryonic Development of the Cerebral Cortex. The ventricular zone (VZ) contains proliferating progenitors of neurons and glia (blue mitotic cells). The first postmitotic, neuronal precursors move above the VZ where they settle in a narrow zone, the preplate (PP). Preplate neurons pioneer cortical axons to both cortical and sub-cortical targets. In-growing axons establish the intermediate zone (IZ). After E13, the preplate splits into the marginal zone (MZ), or future layer I, which contains Cajal-Retzius cells, and the subplate (SP), a transient population of neurons. By E16, the cortical plate thickens as precursors of large, output neurons (orange cells), as well as of some interneurons, migrate along radial glia (navy cells) to establish the neuronal layers. A large population of interneurons (green cells), nearly 80% in the developing murine neocortex, migrate into the developing cortex from the basal forebrain in a trajectory that is tangential to the radial plane. These neurons migrate into the emerging cortical laminae along axons in the IZ and the MZ. Neurogenesis (blue and yellow mitotic cells) continues in both the VZ and the subventricular zone (SVZ), a zone of dividing cells above the VZ which generates neuronal precursors that migrate rostrally, forming the rostral migratory stream.

Figure 4

Preplate Neurons Undergo Changes in Cell Polarity Prior to Preplate Separation and Cortical Plate Formation. Beginning on E12.5, preplate neurons undergo transient changes in polarity, as randomly oriented neurons align with the radial axis by E13.5, forming a transiently columnar pseudolayer just prior to the separation of the preplate into the marginal zone and subplate. Red, Golgi. (Adapted from (Schneider et al., 2010).)

Figure 5

Granule Cell Development and Radial, Glial Guided Migration in the Postnatal Cerebellum. During postnatal cerebellar development, granule cell progenitors (GCPs) proliferate in the outer region of the external granule layer (EGL) (1). After exiting the cell cycle, GCPs move into the lower aspect of the EGL and commence differentiation, extending bipolar axons, the parallel fibers (2). Thereafter, the cell soma extends a leading process in the direction of migration (3), trailing a “T-shaped” axon behind, and migrates along Bergmann glial fibers (BF) through the molecular layer and Purkinje cell layer (4–6) into the internal granular layer, where they form dendrites and synaptic connections (7). (P, Purkinje cell; B, Bergmann glial cell; G, mature granule neuron.) (Drawing provided by Dr. Carol A. Mason).

Figure 6

Cellular Mechanisms of Radial, Glial-Guided Migration in the CNS. (1) During radial, glial-guided migration of CNS neurons, the neuron polarizes and forms a leading process (LP) in the direction of migration. The centrosome (C) and golgi apparatus (not shown) are localized forward of the nucleus (N), which is enwrapped in a perinuclear tubulin cage (PNC). Microtubules (MT) extend from the centrosome into the leading process, and F-actin and acto-myosin motors (AM) are enriched in the proximal portion of the leading process. A specialized interstitial adhesion junction (IJ) forms beneath the neuronal soma and punctae adherentia (PA) form beneath short filopodia (F) that eminate from the leading process and enwrap the glial fiber (GF). (2) The migration cycle involves forward movement of the centrosome (C) prior to forward movement of the nucleus (N) and soma. Swelling of the proximal area of the leading process occurs, and dissolution of the interstitial junction is required to release adhesion from the glial fiber and allow the neuron to glide forward. After the nucleus and soma move forward as the neuron takes a step along the glial fiber (3), a new interstitial adhesion junction forms and the migration cycle starts again so that migration continues in a cyclical, saltatory manner. (Adapted from (Solecki et al., 2006).)

Figure 7

Rho GTPase Signaling Involved in Radial Migration. Some of the key molecules implicated in Rho GTPase signaling that play a role in radial migration, and potential interactors, are shown here (see text for details).