From migration to settlement: the pathways, migration modes and dynamics of neurons in the developing brain - PubMed (original) (raw)
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From migration to settlement: the pathways, migration modes and dynamics of neurons in the developing brain
Yumiko Hatanaka et al. Proc Jpn Acad Ser B Phys Biol Sci. 2016.
Abstract
Neuronal migration is crucial for the construction of the nervous system. To reach their correct destination, migrating neurons choose pathways using physical substrates and chemical cues of either diffusible or non-diffusible nature. Migrating neurons extend a leading and a trailing process. The leading process, which extends in the direction of migration, determines navigation, in particular when a neuron changes its direction of migration. While most neurons simply migrate radially, certain neurons switch their mode of migration between radial and tangential, with the latter allowing migration to destinations far from the neurons' site of generation. Consequently, neurons with distinct origins are intermingled, which results in intricate neuronal architectures and connectivities and provides an important basis for higher brain function. The trailing process, in contrast, contributes to the late stage of development by turning into the axon, thus contributing to the formation of neuronal circuits.
Figures
Figure 1.
Switching between migratory modes (radial and tangential). Some neurons, such as pontine neurons, initially migrate radially towards the pial surface (1), then migrate tangentially (2), and finally radially again away from the pia (3).
Figure 2.
The relationship between the two migratory streams of cortical interneurons. A, Coronal section showing the leading head of interneuron migratory streams in an E13.5 Nkx2.1 CreERT2; Ai9 cortex, in which tamoxifen was applied at E9.5. While the migratory streams in the MZ and IZ/SVZ are separated at the lateral part of the cortex, they appear to join at the medial part located at the leading head, a feature presumably reflecting the latero-medial sequence of cortical development (Kita et al., unpublished results). These neurons are likely the earliest generated interneurons, since the generation of interneurons begins at E10.5–E11.5 (Hevner et al., 2004).30) Given that most CGE-derived interneurons are generated later than E13.5 and do not express Nkx2.1, these neurons must be mainly of MGE origin. B, A coronal section of an E15.5 GAD67-GFP mouse cortex. Migratory streams in the MZ and SVZ or IZ are segregated in their entire course. These migrating neurons should include both MGE and CGE-derived neurons. C and D, Schematics illustrating the migratory streams of interneurons in the cortex at E13.5 (C) and E15.5 (D). Medial is to the left. Scale bars, 100 µm.
Figure 3.
Time-lapse sequence of a migrating interneuron in the MZ of a flat mount preparation of an E15.5 cortex visualized by electroporation of GFP at E12.5.13) Arrows indicate the same neuron at different time points. In frames 9 : 20 and 10 : 00, the arrowheads indicate a leading process transforming into a trailing process. In frame 17 : 20, the arrow and arrowhead indicate a soma and a swelling, respectively. The numbers in the lower right or upper left corners indicate time. The panel in the lower right indicates tracking of the cell, with arrows pointing along the migratory directions. Scale bars, 50 µm and 25 µm (inset).
Figure 4.
Dynamics of the nucleus and Golgi apparatus at the bifurcating point of the leading process in living embryo. A, A schematic illustration of in vivo imaging in mouse embryos. See Yanagida et al., 201219) for details. B, Time-lapse sequence showing the swinging behavior of a nucleus with V-shaped morphology at a bifurcating point of the leading process. Neurons were labeled by electroporation of nuclear localization sequence (nls)-EGFP (green) and GAP-tdTomato (magenta). Arrowhead points to a budding form of the nucleus. The arrow points to the tip of the retracting process. Processes originating from cells that were excluded from this analysis are covered by black rectangles. C, Time-lapse sequence showing nucleokinesis near a branching point. Neurons were labeled by the electroporation of nls-EGFP (green) and GAP-tdTomato (magenta). The filled arrowheads indicate the nucleus, while the open arrowheads point to the branch that will eventually retract, with the larger arrowheads pointing to the tip of the branch. Two leading processes were extending when the nucleus reached the branching point (t = 0 : 20). Subsequently, the nucleus directly entered one of the leading processes (t = 0 : 30), followed by retraction of the other (t = 0 : 50). Neurons that were excluded from the analysis are covered by black rectangles. D, Time-lapse sequence showing the dynamics of the Golgi apparatus at the bifurcating point of the leading process. The Golgi apparatus is shown as a white spot (arrowhead). Note that in most cases, the Golgi apparatus moved into a branch (t = 1 : 44) before the nucleus did. E, A model of the dynamics of subcellular organelles at the branching point of migrating cortical interneurons. At the branching point of the leading process (E2), the Golgi/centrosome complex moves into a leading process branch (E3) before the nucleus does (E4). Translocation of the Golgi/centrosome complex into a leading process appears to be a key step for selecting the new direction of migration. Elapsed time is indicated at the top-left corners (hr : min) in (B–D). Scale bars, 10 µm (B and D) and 50 µm (C).
Figure 5.
Schematic illustration showing migration of cerebellar neurons. A, During embryonic stages Purkinje cells (PC) and Golgi cells (GC) originating from the cerebellar ventricular zone migrate radially towards the pial surface, while granule cell (GrC) precursors and deep cerebellar neurons (CN) originating from the upper rhombic lip migrate tangentially beneath the pial surface. Unipolar brush cells (UBC), which also originate from the upper rhombic lip, also migrate tangentially but through the white matter. B, During the postnatal development granule cells that initially migrate tangentially change the direction of migration and initiate radial migration. They migrate past the Purkinje cells to settle in the inner granule cell layer.
Figure 6.
Migratory routes of precerebellar neurons. Most precerebellar neurons originate from the lower rhombic lip (lRL) and migrate tangentially (A). Those that are fated to form the pontine grey nucleus (PGN) and the reticulo-tegmental nuclei of the pons (RTN) migrate through the anterior extramural stream (AES), while those that are fated to form the lateral reticular nucleus (LRN) and the external cuneatus nucleus (ECN) migrate along the posterior extramural stream (PES). The former migrate circumferentially beneath the pia matter and change the direction of migration from tangential to radial near the midline (B), mainly before crossing the ventral midline. The latter also migrate circumferentially and change the direction of migration from tangential to radial after crossing the midline (C). A is a lateral view, and B and C show cross sections of the hindbrain. Green cells represent migrating neurons and red lines represent fibers of radial glia.
Figure 7.
A schematic illustrating the mode of two-step neuronal migration. The centrosome/Golgi complex (black dot) first moves ahead (1–3) and is followed by translocation of the nucleus (3–4). The nucleus is pushed forward by myosin, which is localized at the rear (3–5). Modified after Schaar and McConnell, 2005.50)
Figure 8.
A schematic illustration showing intermixing of neurons from different sites of origin as a result of switching the migratory mode. A, One neuron first migrates radially toward the pial surface (1), then tangentially (2), and finally radially back towards the ventricular surface (3) a distance away from the site of origin. Another neuron simply migrates towards the pial surface without much tangential displacement (4). B, Intermixing of different types of neurons as a result of tangential migration. Progenitors in different locations give rise to different types of neurons. Tangential migration of neurons, as shown in (A), allows neurons (blue) to move into a region where different types of neurons (red) are located.
Figure 9.
Axon elongation that follows neuronal migration. A, A schematic illustrating axon elongation for four types of neurons. A-1, Cerebellar granule cells first migrate tangentially through the external granule layer while extending a leading process in their front and a trailing process in their rear. Then, they switch their mode of migration from tangential to radial to migrate toward the internal granular layer along a radially aligned process of Bergman glial cells (red). The original leading and trailing processes that are left behind turn into the axon. A-2, PN neurons first migrate tangentially beneath the pial surface of the hindbrain while extending a leading process in their front. Upon arriving at the presumptive nuclear region, some PN neurons begin to migrate radially along the radial glial fiber (red). The original leading process, which has become the trailing process as a result of switching to radial migration, may turn into the axon. A-3, Cortical excitatory neurons exhibit a multipolar shape soon after departure from the ventricular zone. Then, they elongate a tangentially oriented process, which is followed by radial migration of the neuron along a radial glial fiber (red). The combined trailing process and tangential process turn into the axon. A-4, Cortical interneurons that have migrated tangentially in the MZ and descended into the CP assume a multipolar shape. The axon emerges from these non-polarized cells. B, Time-lapse sequence of the radial migration of a PN neuron (arrow). This neuron migrates tangentially from left to right. Upon arriving at the presumptive nuclear region, it slows down its migration and a new process (asterisk) emerges in a direction different from the direction of migration (t = 160), which induces radial migration of the cell (t = 640). Time in min is shown in the upper right corner of each panel. C, Extension of a radially oriented process from a PN neuron elongating along the radial fiber. Left panel shows EYFP-labeled PN neurons in the presumptive nuclear region; middle panel shows immnoreactivity of nestin, marker for radial glia cells; and right panel shows a merged view. D, Extension of an axon-like process from a sea urchin-like cortical interneuron. Time-lapse imaging began at P0.5. An axon-like process is marked in pink. Elapsed time after the onset of imaging (hr) is indicated on the upper right corners. Dashed lines indicate the pial surface. (i–iv) High magnification of the areas demarcated by blue or green rectangles show a sea urchin like-cell that has just initiated an axon-like process headed by a growth cone (i) and growing tips of axon-like processes (ii–iv). Modified after Watanabe and Murakami, 2000,16) Kawauchi et al. 20097) and Yamasaki et al., 2010.87) Scale bars: 30 µm (B and D), 20 µm (C), 10 µm (inset in D).
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