Molecular Diversity Subdivides the Adult Forebrain Neural Stem Cell Population

Abstract

Neural stem cells (NSCs) in the ventricular domain of the subventricular zone (V-SVZ) of rodents produce neurons throughout life while those in humans become largely inactive or may be lost during infancy. Most adult NSCs are quiescent, express glial markers, and depend on Notch signaling for their self-renewal and the generation of neurons. Using genetic markers and lineage tracing, we identified subpopulations of adult V-SVZ NSCs (type 1, 2, and 3) indicating a striking heterogeneity including activated, brain lipid binding protein (BLBP, FABP7) expressing stem cells. BLBP+ NSCs are mitotically active components of pinwheel structures in the lateral ventricle walls and persistently generate neurons in adulthood. BLBP+ NSCs express epidermal growth factor (EGF) receptor, proliferate in response to EGF, and are a major clonogenic population in the SVZ. We also find BLBP expressed by proliferative ventricular and sub-ventricular progenitors in the fetal and postnatal human brain. Loss of BLBP+ stem/progenitor cells correlates with reduced neurogenesis in aging rodents and postnatal humans. These findings of molecular heterogeneity and proliferative differences subdivide the NSC population and have implications for neurogenesis in the forebrain of mammals during aging.

Adding a spatial dimension to postnatal ventricular-subventricular zone neurogenesis

“…B1 astrocytes represent the bona fide NSCs of the mature SVZ (Doetsch et al, 1999) and can be further classified into quiescent (B1) and active (B1a) (Fig. 5B) based on their expression of the RGC markers BLBP (Fabp7), nestin and EGF receptor, which are absent during the quiescent phase and expressed following activation (Codega et al, 2014;Giachino et al, 2014). Clonal analysis suggests that active NSCs generate several rounds of actively proliferating type C cells [also referred to as cycling progenitors or transit amplifying progenitors (TAPs)] before becoming exhausted after a few weeks (Calzolari et al, 2015), while other NSCs become active.…”

The roles and regulation of multicellular rosette structures during morphogenesis

“…These rosettes are found in the ventral subventricular zone (V-SVZ, see Glossary, Box 1) and act as a niche for the neural stem cells (NSCs) that give rise to specific subtypes of olfactory neurons and glial cells (Merkle et al, 2007;Giachino et al, 2014). The rosette structure of the V-SVZ is unique to the lateral ventricular wall of the brain and is only found in areas of high neurogenic activity, suggesting that this cellular arrangement plays a crucial role in the adult NSC niche (reviewed by Ihrie and Alvarez-Buylla, 2011).…”

Quiescent neuronal progenitors are activated in the juvenile guinea pig lateral striatum and give rise to transient neurons

“…1B). Interestingly, the vPSB was highly enriched in astrocytes that, like neurogenic astrocytes of the embryonic and adult neurogenic niches, expressed GFAP (Doetsch et al, 1999;Garcia et al, 2004), BLBP (Anthony et al, 2004;Giachino et al, 2013), Vimentin (Doetsch et al, 1999;Schnitzer et al, 1981) andPAX6 (Götz et al, 1998;Maekawa et al, 2005) (Fig. 2B,C; supplementary material Fig.…”