Research Article

Extensive migration of young neurons into the infant human frontal lobe

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Science  07 Oct 2016:
Vol. 354, Issue 6308, aaf7073
DOI: 10.1126/science.aaf7073
  • Widespread neuronal migration into the human frontal lobe continues during postnatal life.

    (A) Sagittal schematic of the newborn forebrain shows prominent collections of young migratory neurons (illustrated in green) adjacent to the lateral ventricle (LV) and in the overly­ing white matter. Directional axes: D, dorsal; A, anterior. (B and C) DCX+ cells coexpress GABA and GAD67, markers of inhibitory interneurons (marked by arrows).

  • Fig. 1 Migrating young neurons in the infant frontal lobe are widely distributed in four tiers.

    (A) Serial Nissl-stained sections (taken at birth) reveal cell-dense collections around the anterior body of the lateral ventricle (black arrows, defined here as the Arc); LV, lateral ventricle. (B and C) The cells in these densities (yellow arrows) and next to the ventricular wall express DCX. (D) Coronal sections (38 GW) showing cell densities close to the ventricular wall (eyebrow-shaped, black arrows). (E) Dense aggregates of DCX+ cells around the walls of the lateral ventricles (white arrows), around blood vessels (red arrowhead), and in the parenchyma within the Arc (gray arrows). (F to I) DCX+ cells also express PSA-NCAM; (F) and (G) show cells within the Arc; (H) and (I) show cells next to the ventricular walls. (J and K) Schematic drawings of traced DCX+ cells (in green) illustrating how cells within the Arc are organized into four tiers (see text). Blood vessels are shown in red; light green clusters correspond to DCX+ cellular densities seen in (B) and (E). Scale bars, 2 mm [(A) and (B)], 50 μm (C), 1 mm (D), 25 μm [(F) to (I)].

  • Fig. 2 Arc cells have ultrastructural features of migrating young neurons.

    (A) Toluidine blue staining of a semithin sagittal section from a 1-month-old brain showing a chain of cells around a blood vessel in tier 3 (see Fig. 1). Locations of images in (B) and (C) are shown. (B) Electron microscopy shows that this chain is made up of elongated cells with ultrastructural features of young migrating neurons; the chain is flanked by astrocytes (As) whose expansions (arrows) contain intermediate filaments. (C) An elongated migrating neuron (outlined in pink) next to a microglial cell (Mg). Migrating young neurons (N) frequently had an elongated morphology, a leading process, polyribosomes, and no intermediate filaments. (D) The cytoplasm of astrocytes is lighter and contains intermediate filaments. (E and F) 3,3′-Diaminobenzidine (DAB) staining of semithin coronal sections (adjacent to those used for electron microscopy) shows DCX expression within the chain and GFAP expression surrounding them; the counterstain is toluidine blue. Scale bars, 50 μm (A), 10 μm (B), 2 μm (C), 200 nm (D), 15 μm [(E) and (F)].

  • Fig. 3 Migration and directionality of young neurons in the infant brain.

    (A) Boxed region shows area of the neonatal brain that was imaged in (B) and (C) in the cingulate gyrus. (B) DCX+ adenoGFP-labeled cell with migratory morphology. (C) Time-lapse sequence (15 hours) of adenoGFP-labeled cell revealing leading process extension, nucleokinesis, and trailing process retraction. This cell traveled ~100 μm, migrating anteriorly in the sagittal plane. (D and E) Vector mapping of orientation of DCX+ cell leading processes, in sagittal and coronal sections; note how directionality changes in the different tiers. See figs. S6 and S7 for complete analysis. (D′ and E′) Red arrowheads indicate the modal (most frequent) direction of DCX+ cells’ leading process. (F) Spatiotemporal mapping of DCX+ cells in coronal cortical sections; between birth and 1.5 months, many DCX+ cells have moved from the periventricular and parenchymal regions into the developing cortex of the cingulate and superior frontal gyrus. DCX+ cells then rapidly decrease at 3 and 5 months, but a few DCX+ cells with clear migratory morphology remain at 7 months. (G) Quantification of DCX+ cells in the cingulate gyrus (white matter and gray matter). Scale bars, 10 μm (B), 50 μm (C), 5 mm (F). Directional axes: D, dorsal; L, lateral; A, anterior.

  • Fig. 4 Interneuron and subpallial marker expression in migrating DCX+ cells in the infant brain.

    (A) Schematic of coronal section indicating the Arc area that was analyzed at the dorsolateral edge of the ventricle; see fig. S2 for marker expression next to the walls of the lateral ventricle. (B to D) DCX+ cells express GAD67, GABA, and the cytokine receptor CXCR4 present in migrating interneurons. (E to H) Subpopulations of DCX+ cells express different transcription factors associated with ventral telencephalic origin, including Sp8, COUP-TFII, Nkx2.1, or Lhx6 associated with the CGE or MGE. (I) Quantification of DCX+ cells expressing Sp8, COUP-TFII, Nkx2.1, and Lhx6. Bars show means ± SEM of counts performed on three or four individual cases. (J and K) DCX+ cells do not express Olig2 or Sox2. Scale bar, 20 μm.

  • Fig. 5 Interneuron subtype development in the cingulate gyrus.

    (A to E) Many DCX+ cells in the neonatal cingulate cortex express GAD67 (A), and subpopulations also coexpress interneuron subtype markers: calbindin (CalB) (B), neuropeptide Y (NPY) (C), somatostatin (SST) (D), and calretinin (CalR) (E). DAPI, 4′,6-diamidino-2-phenylindole. Yellow arrows point to DCX+ cells that coexpress the indicated subtype markers. (F) Spatiotemporal distribution of interneuron subtypes from birth to 24 years. NPY+ and SST+ cells are located primarily in the white matter at birth but shift to the cortex over time. CalR+ and CalB+ are already expressed in cells throughout the cortex at all ages, but their number continues to increase during the first five postnatal months. (G) Stereological quantification of interneuron subtypes in the cingulate cortex from birth to 24 years. The number of NPY+, SST+, CalB+, and CalR+ cells increases between birth and 5 months, coinciding with the arrival of DCX+ cells in the cingulate cortex (see Fig. 3G). Scale bars, 50 μm [(A) to (E)], 2 mm [(F), 1 day to 6 years], 1 mm [(F), 24 years]. Directional axes: D, dorsal; L, lateral.

  • Fig. 6 Migratory streams of young neurons in the frontal lobe of the early postnatal human brain.

    In the frontal lobe of the neonatal human brain, cut in sagittal and coronal planes in this schematic, large numbers of young migrating neurons persist (shown in green) (see Figs. 1 to 3). Multiple concentric tiers of migrating cells are observed around the anterior pole of the lateral ventricle (see Fig. 1). Close to the ventricular wall, migrating young neurons are largely oriented tangentially; dense subpopulations are also clustered around blood vessels (red). Farther out, young neurons are more dispersed, many now oriented radially; they appear to migrate long distances through the developing white matter to reach the cortex. Ventrally, we also illustrate the RMS and the MMS, which target the olfactory bulb and medial prefrontal cortex, respectively (20).

Supplementary Materials

  • Extensive migration of young neurons into the infant human frontal lobe

    Mercedes F. Paredes, David James, Sara Gil-Perotin, Hosung Kim, Jennifer A. Cotter, Carissa Ng, Kadellyn Sandoval, David H. Rowitch, Duan Xu, Patrick S. McQuillen, Jose-Manuel Garcia-Verdugo, Eric J. Huang, Arturo Alvarez-Buylla

    Materials/Methods, Supplementary Text, Tables, Figures, and/or References

    Download Supplement
    • Materials and Methods
    • Figs. S1 to S12
    • Tables S1 to S4
    • Captions for movies S1 to S5
    • References

    Images, Video, and Other Media

    Movie S1
    3D rendering of DCX+ cells (green) in Arc strip ensheathed by GFAP+ fibers (pink) at 1.5 months.
    Movie S2
    Time-lapse imaging showing a migrating neuron in a sagittal cortical slice from a brain at birth. Area imaged is developing white matter of cingulate. Note cell (*) is traveling in anterio-dorsal direction. Movie spans 18 hours.
    Movie S3
    Time-lapse imaging showing a migrating neuron in a coronal cortical slice from a brain at birth. Area imaged is at the dorsolateral edge of the lateral ventricle, within the Arc region. Movie shows a migrating neuron (*) leaving the dense cell collection. Movie spans 24 hours.
    Movie S4
    Time-lapse imaging showing migrating neuron in a coronal cortical slice from a brain at birth. Area imaged is at the dorsolateral edge of the lateral ventricle, within the Arc region. Movie shows
    Movie S5
    Schematic animation of three-dimensional rendering of postnatally migrating neurons in the infant brain. Arc-orange, SVZ and RMS-magenta, MMS-green.

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