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. 2011 Apr;21(4):748-55.
doi: 10.1093/cercor/bhq142. Epub 2010 Aug 16.

Timing of cortical interneuron migration is influenced by the cortical hem

Giuliana Caronia-Brown  1 , Elizabeth A Grove
Affiliations

Timing of cortical interneuron migration is influenced by the cortical hem

Giuliana Caronia-Brown et al. Cereb Cortex. 2011 Apr.

Abstract

Cerebral cortical γ-aminobutyric acid (GABA)ergic interneurons originate from the basal forebrain and migrate into the cortex in 2 phases. First, interneurons cross the boundary between the developing striatum and the cortex to migrate tangentially through the cortical primordium. Second, interneurons migrate radially to their correct neocortical layer position. A previous study demonstrated that mice in which the cortical hem was genetically ablated displayed a massive reduction of Cajal-Retzius (C-R) cells in the neocortical marginal zone (MZ), thereby losing C-R cell-generated reelin in the MZ. Surprisingly, pyramidal cell migration and subsequent layering were almost normal. In contrast, we find that the timing of migration of cortical GABAergic interneurons is abnormal in hem-ablated mice. Migrating interneurons both advance precociously along their tangential path and switch prematurely from tangential to radial migration to invade the cortical plate (CP). We propose that the cortical hem is responsible for establishing cues that control the timing of interneuron migration. In particular, we suggest that loss of a repellant signal from the medial neocortex, which is greatly decreased in size in hem-ablated mice, allows the early advance of interneurons and that reduction of another secreted molecule from C-R cells, the chemokine SDF-1/CXCL12, permits early radial migration into the CP.

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Figures

Figure 1.
Figure 1.
Genetic ablation of the hem results in premature tangential migration of interneurons into cortex. (A-H) Coronal sections through E12.5 (A-B) and E13.5 (C,H) brains, processed with ISH for the genes indicated. Arrowheads mark the extent of interneuron tangential migration into the cortical primordium through the SVZ/IZ and the MZ. (I,J) Distance traveled from the corticostriate boundary in mutants and controls at E12.5 (I) and E13.5 (J). Asterisks (A-H) indicate the corticostriate boundary, the point of entry into cortex. (C-F) Low (C,D) and higher (E,F) magnification of Erbb4-expressing interneurons. The SVZ/IZ stream of interneurons extends further dorsally into the cortical primordium in hem-ablated compared with control brains (C-F). Higher magnification shows a similar difference in the MZ migratory stream (E,F). (G,H) Lhx6-expressing interneurons also extend further in hem-ablated than control cortices. (I,J) At E13.5 (J), but not at E12.5 (I), the migration front of Lhx6-expressing interneurons in the SVZ/IZ has reached significantly further into the cortical primordium in the mutant compared with the control at rostral, mid, and caudal levels in the brain. Distance traveled by Lhx6-expressing interneurons from the corticostriate boundary in microns is expressed as means ± standard error of the mean. Three asterisks represent P < 0.005. Abbreviations: ch, cortical hem; SVZ/IZ; MZ; MGE, medial ganglionic eminence; LGE, lateral ganglionic eminence. Scale bar, 100 μm (A,B, and E-H), 250 μm (C,D).
Figure 2.
Figure 2.
Distribution of major subpallial guidance cues for interneurons is similar in control and hem-ablated brains. (A-F) Coronal sections of E13.5 brains, processed with FISH for class III Semaphorins (Sema3a and Sema3f) (A-D) and Neuregulin1 (Nrg1) (E,F). Arrowheads in (A-F) mark the corticostriate boundary as a landmark for evaluating gene expression patterns. (A-F) Expression patterns of Sema3a, Sema3f, and Nrg1 appear highly similar between control and hem-ablated mice in the developing striatum (St) and neocortex (ncx). An exception is the cortical hem (ch) in which Nrg1 is strongly expressed in the control (E) but absent, as expected, in the hem-ablated mouse (F). Double FISH for Erb-B4 (green), marking interneurons, and Nrg1 (red) (E',F'). Scale bar, 250 μm (A-F).
Figure 3.
Figure 3.
Corticostriate boundary is properly positioned in hem-ablated mice. (A-D) Coronal sections of E13.5 brains, processed with ISH for Sfrp2 and Tgfα. Arrowheads mark the position of the corticostriate boundary, or “anti-hem,” which appears similarly positioned between the lateral ganglionic eminence and cortical primordium in control and hem-ablated brains. Anti-hem expression of Sfrp2 and Tgfα appears equivalently strong in both brains. Abbreviations: ncx, neocortex; LGE, lateral ganglionic eminence. Scale bar, 230 μm (A-D).
Figure 4.
Figure 4.
Ablation of the hem results in a reduction of medial cortex. (A-F) Coronal sections of E13.5 brains, processed with ISH for the genes indicated. (A,B) Emx1 expression fills the neocortical and hippocampal primordia in a control brain (A). The hem-ablated brain (B) has no hippocampus, but the cortical primordium is reduced in length more than is accounted for hippocampal loss (C,D). Arrowheads mark the relatively Wnt7b-poor medial portion of the neocortical primordium (lines in C). This region is virtually absent in the hem-ablated mouse (D, arrowhead). (E,F) The expression pattern of Bmpr1b distinguishes the hippocampal primordium as a more lightly stained territory than the rest of the cortex (E). This domain is missing as expected in the mutant (F). Abbreviations: ncx, neocortex; hp, hippocampal primordium; ch, cortical hem. Scale bar, 250 μm (A-F).
Figure 5.
Figure 5.
Radial migration of interneurons in hem-ablated cortex. (A-B) E15.5 coronal sections processed with ISH to label Lhx6-expressing interneurons. Labeled cells are more abundant in the CP of the hem-ablated brain (A,B, arrowheads) as well as the uIZ. White arrowheads indicate cells apparently detaching from the marginal zone (MZ). (C) The number of interneurons occupying the CP and the uIZ was significantly higher in hem-ablated mice than in control brains. Data are expressed as means ± standard error of the mean. *** indicates P < 0.005. Abbreviations: SVZ, subventricular zone; lIZ, lower intermediate zone. Scale bar, 100 μm (A,B).
Figure 6.
Figure 6.
Premature radial migration correlates with loss of Cxcl12-positive C-R cells. (A,B) Coronal sections of E17.5 brains processed with ISH for Cxcl12. Arrowheads in (A) mark Cxcl12-expressing C-R cells in the MZ of the dorsal neocortical primordium, which are missing from the same region of hem-ablated cortex (B). (C-D) Lhx6-expressing interneurons are more profuse in the CP and uIZ of hem-ablated brains compared with controls, whereas fewer interneurons appear in the lower intermediate zone (lIZ) and SVZ/IZ of the mutant. Abbreviation: mng, meninges. Scale bar, 50 μm (A,B), 100 μm (C,D).
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