Anatomy of the brain neurogenic zones revisited: Fractones and the fibroblast/macrophage network

Abstract

Cytogenesis in adult peripheral organs, and in all organs during development, occurs nearby basal laminae (BL) overlying connective tissue. Paradoxically, cytogenesis in the adult brain occurs primarily in the subependymal layer (SEL), a zone where no particular organization of BL and connective tissue has been described. We have reinvestigated the anatomy of the area considered the most neurogenic in the adult brain, the SEL of the lateral ventricle, in zones adjacent to the caudate putamen, corpus callosum, and lateral septal nucleus. Here, we report structural (confocal microscopy using laminin as a marker) and ultrastructural evidence for highly organized extravascular BL, unique to the SEL. The extravascular BL, termed fractones because of their fractal organization, were regularly arranged along the SEL and consisted of stems terminating in bulbs immediately underneath the ependyma. Fractones contacted local blood vessels by means of their stems. An individual fractone engulfed in its folds numerous processes of astrocytes, ependymocytes, microglial cells, and precursor cell types. The attachment site (base) of stems to blood vessels was extensively folded, overlying large perivascular macrophages that belong to a fibroblast/macrophage network coursing in the perivascular layer and through the meninges. In addition, collagen-1, which is associated with BL and growth factors during developmental morphogenetic inductions, was immunodetected in the SEL and particularly regionalized within fractones. Because macrophages and fibroblasts produce cytokines and growth factors that may concentrate in and exert their effect from the BL, we suggest that the structure described is implicated in adult neurogenesis, gliogenesis, and angiogenesis.

SPARC is expressed by macroglia and microglia in the developing and mature nervous system

“…3). The SVZ contains specialized structures of extravascular basal lamina, termed fractones, that contain laminin and collagen (Mercier et al, 2002). As a highly conserved base- ment membrane molecule (Fitzgerald and Schwarzbauer, 1998;Bradshaw and Sage, 2001;Martinek et al, 2002), SPARC may be involved in the assembly and maintenance of fractones by regulating the production of ECM molecules such as laminin (Kamihagi et al, 1994;Weaver et al, 2006) and collagen (Francki et al, 1999;Bradshaw et al, 2003b).…”

The microenvironment of the embryonic neural stem cell: Lessons from adult niches?

“…Endothelial cells in coculture with neural stem cells were found to release soluble factors that increase self-renewal of the stem cells, an effect that is likely to be mediated through VEGF-C/VEGFR-3 and/or pigment epithelium derived factor (PEDF) (Shen et al, 2004;Le Bras et al, 2006;Ramirez-Castillejo et al, 2006) Additionally, basal-lamina-like extensions (called fractones) extend from blood vessels in the SEZ and make contact with all cells in the niche providing a source of ECM containing collagen-IV, laminins, perlecan, nidogen and, in some cases, heparan sulfate proteoglycans (HSPG). These likely send important signals to the stem cells that may include the presentation of FGF-2, which binds to fractone HSPG (Mercier et al, 2002;Kerever et al, 2007).…”

Endothelial cells promote neural stem cell proliferation and differentiation associated with VEGF activated Notch and Pten signaling

“…In adults, neurogenesis occurs near blood vessels, and neural stem cells are closely associated with endothelial cells in both the hippocampus and subventricular zone (Palmer et al, 2000;Capela and Temple, 2002). Basal laminae arising from blood capillaries are thought to concentrate growth factors secreted from the neural stem cell microenvironment via binding to heparan sulfate glycosaminoglycans (Mercier et al, 2002). Endothelial cells are known to synthesize numerous basal lamina elements and growth factors involved in neurogenesis, such as brain-derived neurotrophic factor and vascular endothelial growth factor (VEGF) (Mabie et al, 1999;Leventhal et al, 1999;Jin et al, 2002).…”