Guiding neuronal cell migrations

Abstract

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.

Figure 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.

Figure 2.

Leading process dynamics in cortical migrating neurons. (A) Early generated pyramidal cells migrate independently of radial glia fibers by translocating their soma toward the meninges using a springlike mechanism (a). (B) As the cerebral cortex grows, the distance between the ventricular zone (VZ) and the marginal zone (MZ) increases, and pyramidal cells use locomotion to reach the cortical plate (CP). Pyramidal cells go through a multipolar state (e) before attaching to the radial glial process and continue their migration toward the cortical plate (c). Cortical interneurons initially migrate tangentially through the cortex in defined streams (A and B), without invading the cortical plate. Then, eventually, they move radially to allocate in a particular cortical layer. The leading process of these cells develops several branches, which are used to modify their trajectory (d and e). Projection neurons and interneurons born at the same time end up occupying the same layers (red colored nuclei represent cells born at the same time). (SVZ) subventricular zone; (VZ) ventricular zone; (V–VI) cortical layers V and VI.

Figure 3.

Nucleokinesis in migrating neurons. Nucleokinesis involves both perinuclear and nucleus translocation. First, the perinuclear dilatation containing the centrosome and the Golgi apparatus move forward. The perinuclear microtubular cage (in green) pulls the nucleus forward until reaching the swelling. Forward pulling forces (green arrow) are complemented by myosin II at the rear, which generates pushing forces (red arrows) to move the nucleus in its characteristic saltatory pattern of nucleokinesis. Many motor proteins and other proteins related to the cytoskeleton are implicated in the process. (N) nucleus.

Figure 4.

Guidance cues and neuronal migration in the telencephalon. The schema shows a coronal slice of the telencephalon at midembryonic stages, in which the main cortical migrations and their guidance cues are indicated. Interneurons born in the medial ganglionic eminence (MGE) migrate tangentially through the subpallium to reach the cortex. Some of these interneurons enter the striatum (striatal interneurons), whereas others continue toward the cortex (cortical interneurons), sorting out through a mechanism that involves Sema3A and Sema3F. Cortical interneurons advance toward the cortex following a corridor of lateral ganglionic eminence (LGE)-derived cells that express CRD-Nrg1 but not semaphorins. Interneurons are guided toward the cortex by a combination of motogenic (HGF/BDNF) and chemoattractive factors (Ig-Nrg1). Once in the cortex, chemokine signaling (Cxcl12) restricts the migration of interneurons through two streams, the marginal zone (MZ) and the subventricular zone (SVZ). Cajal-Retzius cells also use Cxcl12 to disperse through the MZ in opposite direction to interneurons. Cajal-Retzius cells produce Reelin, which along with other factors such as semaphorins, guide the migration of projection neurons. (CP) cortical plate; (GP) globus pallidum; (IZ) intermediate zone; (MZ) marginal zone; (NCx) neocortex; (PCx) piriform cortex; (Str) striatum; (SVZ/VZ) subventricular/ventricular zones.

Figure 5.

Migrating guidepost cells in the developing forebrain. (A, A’) LOT cells are generated early in development at the ventricular zone of the neocortex. They migrate tangentially to the piriform cortex, where they arrive at 3–4 d in advance to the olfactory axonal tract. (B, B’) Glial sling cells derive from the ventricular zone in the medial neocortex at E15.5. They migrate toward the midline to contribute to the formation of the corpus callosum through signaling that involves Slit2. (C, C’) A subpopulation of LGE-derived interneurons migrates ventrally, forming a cellular corridor that expresses CRD-NRG1. These guidepost cells are required for the migration of thalamocortical axons as they extend through the basal telencephalon on their way to the cortex. (GP) globus pallidum; (LGE) lateral ganglionic eminence; (LV) lateral ventricle; (MGE) medial ganglionic eminence; (NCx) neocortex; (OB) olfactory bulb; (PCx) piriform cortex; (P/SP) pallium-subpallium boundary; (S) septum; (Str) striatum.