The Adult Ventricular-Subventricular Zone (V-SVZ) and Olfactory Bulb (OB) Neurogenesis

Abstract

A large population of neural stem/precursor cells (NSCs) persists in the ventricular-subventricular zone (V-SVZ) located in the walls of the lateral brain ventricles. V-SVZ NSCs produce large numbers of neuroblasts that migrate a long distance into the olfactory bulb (OB) where they differentiate into local circuit interneurons. Here, we review a broad range of discoveries that have emerged from studies of postnatal V-SVZ neurogenesis: the identification of NSCs as a subpopulation of astroglial cells, the neurogenic lineage, new mechanisms of neuronal migration, and molecular regulators of precursor cell proliferation and migration. It has also become evident that V-SVZ NSCs are regionally heterogeneous, with NSCs located in different regions of the ventricle wall generating distinct OB interneuron subtypes. Insights into the developmental origins and molecular mechanisms that underlie the regional specification of V-SVZ NSCs have also begun to emerge. Other recent studies have revealed new cell-intrinsic molecular mechanisms that enable lifelong neurogenesis in the V-SVZ. Finally, we discuss intriguing differences between the rodent V-SVZ and the corresponding human brain region. The rapidly expanding cellular and molecular knowledge of V-SVZ NSC biology provides key insights into postnatal neural development, the origin of brain tumors, and may inform the development regenerative therapies from cultured and endogenous human neural precursors.

Figure 1.

Overview of adult mouse olfactory bulb (OB) neurogenesis from the ventricular–subventricular zone (V-SVZ). (A) Sagittal section through mouse head (calvarium is yellow). Neuroblasts (type A cells) born in the V-SVZ of the lateral ventricle (blue) migrate through a network of paths (red) into the rostral migratory stream (RMS), which enters the OB. Cells then leave the RMS (arrows, dashed lines) and migrate radially into the OB. Boxed area is shown enlarged in B. (B) Neuronal layers of OB. Migratory cells depart the RMS and differentiate into granule cells (GC) or periglomerular cells (PGC), which reside in the granule cell layer (GCL) and glomerular layer (GL), respectively (type A cells and differentiated interneurons are red). ORNs (small gray cells) in the olfactory epithelium (OE) project to the GL. The main projection neurons of the OB (mitral cells and tufted cells) are in gray. (C) Artists’ rendition of a chain of migratory type A cells. These chains are ensheathed by glial cells (type B cells, blue) and are associated with clusters of transit-amplifying cells (type C cells, green). (D) Diversity of OB interneurons. Type A cells differentiate into either PGCs or GCs, which can be distinguished by morphology, neurotransmitter (NT) phenotype, and markers. CC, Corpus callosum; Cx, cortex; CB, cerebellum; ORN, olfactory receptor neuron; MCL, mitral cell layer; ep, ependymal cell; TH, tyrosine hydroxylase.

Figure 2.

Cellular composition of the ventricular–subventricular zone (V-SVZ). Coronal section of adult mouse brain is shown in the upper right. The V-SVZ region indicated by the black arrow is shown enlarged in the lower left. Type B1 cells (blue) are the astrocytes that serve as the V-SVZ stem cell. These can divide and produce type C cells (green), which are rapidly dividing, transit amplifying cells. Type C cells give rise to type A cells (red), the migratory neuroblasts. A blood vessel (BV, brown) is shown at the right. The apical surface of type B1 cells has a primary cilium and makes contact with the ventricle, which is at the left. These apical surfaces are found at the center of a “pinwheel” composed of multiciliated ependymal cells (yellow). The V-SVZ can be subdivided into three domains based on the structure and spatial arrangement of type B1 cells: Domain I (apical) contains the type B1 cells apical process and the body of ependymal cells; domain II (intermediate) contains the cell body of most type B1 cells, which are in contact with the type C and A cells; and domain III (basal) contains the B1 cell’s basal process with end-feet on blood vessels (see text for details).

Figure 3.

Interactions of selected ventricular–subventricular zone (V-SVZ) niche factors and cell-intrinsic regulators. Solid arrows indicate the cellular source of a secreted factor, when known. Dotted lines indicate molecular interactions, both known and hypothetical. Blue dotted lines show interactions that may promote SVZ NSC self-renewal. Select transcription factors that may be involved in self-renewal, proliferation control, and specification of different cell types are in italics in the top inset above. Select chromatin-regulators are in the inset second from the top. Select noncoding RNAs are in the third inset from the top (see text for details).