Stromal-Derived Factor-1 (CXCL12) Regulates Laminar Position of Cajal-Retzius Cells in Normal and Dysplastic Brains

Abstract

Normal brain development requires a series of highly complex and interrelated steps. This process presents many opportunities for errors to occur, which could result in developmental defects in the brain, clinically referred to as malformations of cortical development. The marginal zone and Cajal-Retzius cells are key players in cortical development and are established early, yet there is little understanding of the factors resulting in the disruption of the marginal zone in many types of cortical malformation syndromes. We showed previously that treatment with methylazoxymethanol in rats causes marginal zone dysplasia with displacement of Cajal-Retzius cells to deeper cortical layers. Here we establish that loss of activity of the chemokine stromal-derived factor-1 (SDF1) (CXCL12), which is expressed by the leptomeninges, is necessary and sufficient to cause marginal zone disorganization in this widely used teratogenic animal model. We also found that mice with mutations in the main receptor for SDF1 (CXCR4) have Cajal-Retzius cells displaced to deeper cortical layers. Furthermore, by inhibiting SDF1 signaling in utero by intraventricular injection of a receptor antagonist, we establish that SDF1 signaling is required for the maintenance of Cajal-Retzius cell position in the marginal zone during normal cortical development. Our data imply that cortical layering is not a static process, but rather requires input from locally produced molecular cues for maintenance, and that complex syndromes of cortical malformation as a result of environmental insults may still be amenable to explanation by interruption of specific molecular signaling pathways.

Sema3E/PlexinD1 regulates the migration of hem-derived Cajal-Retzius cells in developing cerebral cortex

“…In this study, we have shown that Sema3E has the capacity to modulate the migration of PlexinD1-positive CR cells triggered by CXCL12/CXCR4 signalling 17,18 . Chemokine signalling through CXCL12/CXCR4 is a common mechanism controlling the migration of several cell types along the body axis, such as hematopoietic progenitor cells 40 , vascular endothelial cells 41 , melanocytes 42 and tumour cells 43,44 .…”

“…Sema3E/PlexinD1 modulates CXCL12/CXCR4 signalling. It is well established that CR cell migration is promoted by CXCL12/ CXCR4 signalling 17,18 . Thus, we aimed to determine whether Sema3E/PlexinD1 might modulate the chemokine signalling (Fig.…”

“…Concerning migration, there are not many molecules identify as regulators of CR cells migration. The chemokine CXCL12 (also known as SDF1) expressed by meningeal cells has been found to be mainly responsible for hem-derived CR cell migration 17,18 as occurs with other neural populations 19 . However, a study by Zarbalis et al 20 , analysing hypomorphic Foxc1 mice with meningeal deficits suggests that meningeal as well as additional non-meningeal factors may modulate the migration of Reelin-positive cortical CR cells in the preplate.…”

A Novel Transient Glutamatergic Population Migrating from the Pallial–Subpallial Boundary Contributes to Neocortical Development

“…This suggests that similar molecular mechanisms might govern tangential migration in the IZ for both GABAergic and CP transient neurons. Indeed, in the MZ, similar cues have been shown to control the migration of GABAergic and CR cells, namely the CXCL12/CXCR4 pathway (Stumm et al, 2003;Borrell and Marín, 2006;Paredes et al, 2006). However, in contrast to GABAergic and CR neurons, CP transient neurons do not appear to be prevented to enter the CP.…”

CXCR4 signaling in the regulation of stem cell migration and development

“…The expression patterns for SDF-1 and CXCR4 in the developing DG, as well as the phenotype of CXCR4 knockout mice, are consistent with a model in which SDF-1 is secreted by meningeal cells that line the route of migrating CXCR4 expressing progenitors, and that progenitors are stalled in their migration when CXCR4 signaling is interrupted. Other neuronal phenotypes observed in CXCR4 knockout mice include defects in the placement of developmentally important Cajal-Retzius cells (Berger et al, 2007;Paredes et al, 2006;Stumm et al, 2003), cortical GABAergic interneurons (Stumm et al, 2007;Stumm et al, 2003;Tiveron et al, 2006) and GnRH secreting forebrain neurons (Schwarting et al, 2006). In all of these situations it appears that the progenitors for these neurons utilize SDF-1 mediated chemoattraction to attain their final positions, and that lack of CXCR4 signaling results in interrupted progenitor migration.…”