Guiding Neuronal Cell Migrations

Neuronal migration is, along with axon guidance, one of the fundamental mechanisms underlying the wiring of the brain. As other organs, the nervous system has acquired the ability to grow both in size and complexity by using migration as a strategy to position cell types from different origins into specific coordinates, allowing for the generation of brain circuitries. Guidance of migrating neurons shares many features with axon guidance, from the use of substrates to the specific cues regulating chemotaxis. There are, however, important differences in the cell biology of these two processes. The most evident case is nucleokinesis, which is an essential component of migration that needs to be integrated within the guidance of the cell. Perhaps more surprisingly, the cellular mechanisms underlying the response of the leading process of migrating cells to guidance cues might be different to those involved in growth cone steering, at least for some neuronal populations.The migration of newly born neurons is a precisely regulated process that is critical for the development of brain architecture. Neurons arise from the proliferative epithelium that covers the ventricular space throughout the neural tube, an area named the ventricular zone (VZ). From there, newly born neurons adopt two main strategies to disperse throughout the central nervous system (CNS), designated as radial and tangential migration (Hatten 1999; Marín and Rubenstein 2003). During radial migration, neurons follow a trajectory that is perpendicular to the ventricular surface, moving alongside radial glial fibers expanding the thickness of the neural tube. In contrast, tangentially migrating neurons move in trajectories that are parallel to the ventricular surface and orthogonal to the radial glia palisade (Fig. 1). Besides their relative orientation, some of the basic mechanisms underlying the movement of cells using each of these two modes of migration are also different. For example, radially migrating neurons often use radial glial fibers as substrate, whereas tangentially migrating neurons do not seem to require their support to migrate. Even so, neurons may alternate from radial to tangential movement and vice versa during the course of their migration. This suggests that both types of migrations share common principles, in particular those directly related to the cell biology of movement (Marín et al. 2006).Open in a separate windowFigure 1.Representative migrations in the developing CNS. Multiple migrations coexist during embryonic development at different areas of the central nervous system. This schema summarizes some of these migrations during the second week of the embryonic period in the mouse. Neurons use tangential and radial migration to reach their final destination; both strategies are used by the same neurons at different stages of development (i.e., cortical interneurons in the forebrain and precerebellar neurons in the hindbrain). (IML) intermediolateral region of the spinal cord; (IO) inferior olive nucleus; (LGE) lateral ganglionic eminence; (LRN) lateral reticular nucleus; (MGE) medial ganglionic eminence; (NCx) neocortex; (OB) olfactory bulb.One of the structures that better illustrates how both types of migrations are integrated during brain development is the cerebral cortex, and so we will primarily refer to studies performed on cortical neurons for this review. The adult cerebral cortex contains two main classes of neurons: glutamatergic cortical projection neurons (also known as pyramidal cells) and GABAergic interneurons. Pyramidal cells are generated in the ventricular zone (VZ) of the embryonic pallium—the roof of the telencephalon—and reach their final position by radial migration (Rakic 2007). In contrast, cortical interneurons are born in the subpallium—the base of telencephalon—and reach the cerebral cortex through a long tangential migration (Corbin et al. 2001; Marín and Rubenstein 2001).The earliest cortical neurons form a transient structure known as the preplate, around embryonic day 10 (E10) of gestation age in the mouse. This primordial layer consists of Cajal-Retzius cells and the first cohort of pyramidal neurons, which will eventually populate the subplate. Cajal-Retzius cells, which play important roles during neuronal migration, arise from discrete pallial sources and colonize the entire surface of the cortex through tangential migration (Bielle et al. 2005; Takiguchi-Hayashi et al. 2004; Yoshida et al. 2006). The next cohort of pyramidal cells forms the cortical plate (CP) by intercalating in the preplate and splitting this primitive structure in a superficial layer, the marginal zone (MZ or layer I), and a deep layer, the subplate. The development of the neocortex progresses with new waves of neurons that occupy progressively more superficial positions within the CP (Gupta et al. 2002; Marín and Rubenstein 2003). Birth dating studies have shown that layers II–VI of the cerebral cortex are generated in an “inside-out” sequence. Neurons generated earlier reside in deeper layers, whereas later-born neurons migrate past existing layers to form superficial layers (Angevine and Sidman 1961; Rakic 1974). In parallel to this process, GABAergic interneurons migrate to the cortex, where they disperse tangentially via highly stereotyped routes in the MZ, SP, and lower intermediate zone/subventricular zone (IZ/SVZ) (Lavdas et al. 1999). Interneurons then switch from tangential to radial migration to adopt their final laminar position in the cerebral cortex (Ang et al. 2003; Polleux et al. 2002; Tanaka et al. 2003).