Radial Glial Neural Progenitors Regulate Nascent Brain Vascular Network Stabilization Via Inhibition of Wnt Signaling

Shang Ma,Zhen Huang,Keling Zang,Heidi Johng,Hyo Jun Kwon,Ben A Barres

doi:10.1371/journal.pbio.1001469

Abstract

Author SummaryThe brain is an energy-intensive organ that consumes about 10 times as much energy per unit volume as the rest of the body. It therefore requires a highly efficient vascular network for oxygen and nutrient delivery, and as a result compromises in blood vessel networks influence a wide array of brain diseases. Our current understanding is that brain-specific neural cell types are involved in shaping its vascular network, but unfortunately little is known about the cellular or molecular mechanisms involved. Using a mouse genetic model, we have found that radial glial cells, a stem cell type well known for its fundamental role in neural circuit formation, also play an unexpected role in brain vessel development. We find that radial glial cells are essential for the stabilization of newly formed blood vessels in the late embryonic brain, and do so in large part through down-regulating canonical Wnt signaling in endothelial cells (which line the interior surface of blood vessels). These findings provide new insight into how new vessels in the brain are normally stabilized and how this process may be compromised and contribute to diseases.

Highlights

The brain consumes approximately10 times as much energy per unit volume as the rest of the body and requires a highly efficient vascular network for oxygen and nutrient delivery as well as waste disposal
To determine how vessel growth in the prenatal murine cortex is regulated, we systematically examined isolectin B4 (IB4) staining from embryonic day12.5 (E12.5) to postnatal day 0 (P0) (Figure 1A–D, and unpublished data)
We show that, during late embryogenesis, radial glial progenitors in the developing cortex participate in this process by regulating the stabilization of nascent brain vascular network, via inhibition of endothelial cell (EC) Wnt signaling

Summary

Introduction

The brain consumes approximately times as much energy per unit volume as the rest of the body and requires a highly efficient vascular network for oxygen and nutrient delivery as well as waste disposal. Cortical blood vessels display a highly complex and hierarchical pattern [1,2], of which a most striking feature is the regularity by which large vessels penetrate the cortex from the pia at right angles. These vessels give off branches and capillaries at various depths, yielding an intricate network. Such stereotypic organizations provide a unique opportunity for understanding how target-specific cell types and signals regulate vascular network formation and patterning and coordinate neural and vascular function during development and throughout life. Little is known about how target neural tissues regulate the later step of vessel stabilization

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Conclusion