The contribution of CXCL12-expressing radial glia cells to neuro-vascular patterning during human cerebral cortex development.

Mariella Errede,Daniela Virgintino,Luisa Roncali,Marco Rizzi,Mirella Bertossi,Francesco Girolamo

doi:10.3389/fnins.2014.00324

Mariella Errede, Daniela Virgintino + Show 4 more

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https://doi.org/10.3389/fnins.2014.00324

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Abstract

This study was conducted on human developing brain by laser confocal and transmission electron microscopy (TEM) to make a detailed analysis of important features of blood-brain barrier (BBB) microvessels and possible control mechanisms of vessel growth and differentiation during cerebral cortex vascularization. The BBB status of cortex microvessels was examined at a defined stage of cortex development, at the end of neuroblast waves of migration, and before cortex lamination, with BBB-endothelial cell markers, namely tight junction (TJ) proteins (occludin and claudin-5) and influx and efflux transporters (Glut-1 and P-glycoprotein), the latter supporting evidence for functional effectiveness of the fetal BBB. According to the well-known roles of astroglia cells on microvessel growth and differentiation, the early composition of astroglia/endothelial cell relationships was analyzed by detecting the appropriate astroglia, endothelial, and pericyte markers. GFAP, chemokine CXCL12, and connexin 43 (Cx43) were utilized as markers of radial glia cells, CD105 (endoglin) as a marker of angiogenically activated endothelial cells (ECs), and proteoglycan NG2 as a marker of immature pericytes. Immunolabeling for CXCL12 showed the highest level of the ligand in radial glial (RG) fibers in contact with the growing cortex microvessels. These specialized contacts, recognizable on both perforating radial vessels and growing collaterals, appeared as CXCL12-reactive en passant, symmetrical and asymmetrical, vessel-specific RG fiber swellings. At the highest confocal resolution, these RG varicosities showed a CXCL12-reactive dot-like content whose microvesicular nature was confirmed by ultrastructural observations. A further analysis of RG varicosities reveals colocalization of CXCL12 with Cx43, which is possibly implicated in vessel-specific chemokine signaling.

Highlights

Radial glial (RG) cells were first described in the developing Central Nervous System (CNS) by Magini and Ramón y Cajal in the late 19th century (Bentivoglio and Mazzarello, 1999)
Their endothelial lining is characterized by a strong reactivity to fundamental metabolic and efflux barrierspecific transporters, such as the glucose transporter isoform 1, Glut-1, and to a member of the ABC (ATP-binding cassette) superfamily, the multidrug transporter P-glycoprotein
Cerebral cortex microvessels are revealed by the endothelial marker CD105, which allows recognition of the growing front of the invading vessels, that is characterized by CD105-reactive endothelial tip cells (Figures 3A,B)

Summary

Introduction

Radial glial (RG) cells were first described in the developing CNS by Magini and Ramón y Cajal in the late 19th century (Bentivoglio and Mazzarello, 1999). Their function as scaffolding for neuroblast migration during cortical histogenesis was postulated and demonstrated by Rakic in the early 1970s (Rakic, 1971, 1972) and at the beginning of the new millennium, their role as neuronal and glial precursors in the developing CNS was definitively demonstrated (Malatesta et al, 2000; Malatesta and Götz, 2013). In human telencephalon, due to the larger size of the cerebral cortex compared with the rodent cortex, a “mature” GFAP-expressing RG precociously develops long shafts that may reach a length of 3000–7000 μm and show early, special vascular relations (Rakic, 1972; Virgintino et al, 1998)

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