Neuronal Migration: An Overview of Modes, Molecular Mechanisms and Model Systems

Abstract

A century ago, Santiago Ramón y Cajal had already postulated that neurons born in specific proliferative zones have to migrate to ensure correct neocortical layering. Today we know that neuronal migration is a common phenomenon in many brain regions and that neurons are often born micrometres to centimetres away from the place they fulfil their function. Mutations that lead to defects in neuronal migration can have devastating consequences like lissencephaly, autism and schizophrenia in humans. With these conditions in mind, neuronal migration has been an area of intense research for more than 50 years. Additionally, neuronal migration phenomena are outstanding models to understand basic themes in cell biology.

The rodent neocortex has been a very popular system to study different modes of neuronal migration. More recently, additional model tissues and organisms have been examined, which help to further expand our knowledge.

The authors provide an overview on different migratory modes and then focus on the cell biology that enables migration in different contexts. They further discuss some experimental challenges that need to be overcome in order to understand neuronal migration in even more depth.

Key Concepts:

  • Actomyosin and microtubules play active roles in neuronal migration. Their exact roles depend on cellular context.

  • Endo‐ and exocytosis of adhesion molecules are crucial for cell–cell and cell–substrate adhesion during migration.

  • Extracellular matrix proteins are important guidance cues for neuronal migration.

  • Neuronal migration is a widespread phenomenon in the central nervous system.

  • The advancement of modern light microscopy should be embraced to observe neuronal migration modes in intact developing organism.

  • Two basic modes of migration exist: radial and tangential migration.

Keywords: neuronal migration; tangential migration; radial glial‐guided migration; cerebral cortex; cerebellar granule neurons; actomyosin; microtubule cage; cell adhesion deadhesion; vertebrate model systems; time‐lapse imaging

Figure 1.

Two modes of neuronal migration. (a) Depiction of a mouse brain at E13.5. The dashed line indicates the plane of coronal section in the middle panel. The brain ventricle is shown in dark grey. The upper red arrow represents tangential migration of Cajal–Retzius cells from the cortical hem. The lower red arrow represents interneuron migration from the medial ganglionic eminence to the cortex. The green arrow represents radial migration of projection neurons from the ventricular to the pial side of the cortex. CER, cerebellum; CH, cortical hem; LGE, lateral ganglionic eminence; MGE, medial ganglionic eminence; OB, olfactory bulb; TEL, telencephalon. (b) Zoom into dashed circle in (a). Tangential migration of interneurons (red) is shown in four steps: (1) migration towards the cerebral cortex in two streams parallel to the ventricular and pial surfaces, (2) interneurons reaching the cortex associate with radial glia cells (grey), (3) radial movement within the cortex by glial‐guided migration and (4) differentiated interneurons at their final position. Radial migration of projection neurons (green) is shown in five steps: (1) the neuron is born at the ventricular surface, (2) multipolar phase of migration, (3) radial movement by glial‐guided migration, (4) terminal translocation and (5) differentiated projection neuron at its final position. MZ, marginal zone; CP, cortical plate; IZ, intermediate zone; SVZ, subventricular zone; VZ, ventricular zone. (c) General anatomy of a radially migrating neuron. The nucleus is depicted in dark grey. The arrow indicates the direction of migration.

Figure 2.

Molecular mechanisms of neuronal migration. (a) Cellular morphology of tangentially migrating interneuron and its organelle arrangement. The image shows interneuron migrating from left to right; stages of movement are depicted from top to bottom. First, the centrosome (grey circle) and the Golgi apparatus (blue) move into the swelling of the leading process. During this movement, the centrosome splits and the Golgi apparatus straightens in direction of migration (grey arrow). Subsequently, the nucleus (dark red) travels towards the centrosome/Golgi. In some cases, the nucleus deforms and moves due to forces exerted by actomyosin contractions (light red) at the cell rear (see main text for details). Leading process morphology: one of the interneuron leading processes branches, gets stabilised and determines the direction of migration for the next migratory cycle; other branches are retracted and new ones are created (grey arrows). (b) Cellular morphology of neurons undergoing glial‐guided migration. Neuronal migration is depicted from bottom to top. The sequence of events is depicted from left to right. First, the centrosome (grey circle) is pulled into the swelling of the leading process by actomyosin contractions (light red). Then the nucleus (green) translocates towards the centrosome (arrow). The zoomed in view of the migrating neuron on the right shows the detailed arrangement of the microtubule cytoskeleton: Microtubules (lines) form a cage‐like structure around the nucleus. The microtubules in the leading process (red lines) are anchored to the centrosome and acetylated and thereby stabilised. The microtubules forming the cage around the nucleus (dark green lines) are not anchored to the centrosome. They are tyrosinated and thereby dynamic (see ‘Actin and microtubules’). Dynein (blue) is also localised around the centrosome as well as in the proximal leading process during glial‐guided migration.

Figure 3.

Turnover of adhesion molecules during glial‐guided migration. Before nucleokinesis, adhesion between neuronal soma (green) and glial cells (grey) is weakened by endocytosis of connexins and N‐cadherin (small bars in the invaginating vesicle). Endocytosis depends on clathrin, dynamin and the Rab family proteins Rab5 and Rab11. Later, connexins and N‐cadherin (bars in vesicles) are exocytosed in the leading process of the neuron. The distribution of adhesion molecules is not uniform. Cx26 (red) is enriched in the swelling of the leading process, whereas Cx43 (yellow) is enriched in the tip of the leading process and its branches. The adhesion molecules in the membrane of RGC were omitted due to the lack of experimental data, but it has been speculated that they form homotypic interaction with adhesion molecules of the neuron. RGC, radial glia cell; Cx26, connexin 26; Cx43, connexin 43.

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Further Reading

Hippenmeyer S (2014) Molecular pathways controlling the sequential steps of cortical projection neuron migration. Advances in Experimental Medicine and Biology 800: 1–24.

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Icha, Jaroslav, and Norden, Caren(Jan 2014) Neuronal Migration: An Overview of Modes, Molecular Mechanisms and Model Systems. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.0000796.pub2]