Type-B cells extend an apical ending that contact the ventricle and a long basal process ending on blood vessels. The number of contacts in the ventricle appears to increase when SVZ proliferation is stimulated (Mirzadeh et al. 2010). Type-B cells are considered to be the NSCs with ultrastructural characteristics of astroglial cells such as irregular contours that profusely fill the spaces between neighbouring cells, a long basal process that terminates on blood vessels and a single primary cilium that reaches the ventricle lumen. The function of the single primary cilium remains to be understood. This cilium can have a mechanosensory function, suggesting that the force of CSF flow itself may exert an influence on the proliferative state of the stem cell (Singla and Reiter 2006). This organelle has also been implicated in Sonic Hedgehog (Shh), Wnt, and PDGF signaling pathways, which are important for the stemness maintenance (Ihrie and Alvarez-Buylla 2011).

Type-B cells express, like type-1 cells in the DG, GFAP, nestin and sox2 but, importantly, not S100B an astrocytic marker also expressed by ependymal cells (Ming and Song 2011). In the RMS, all type-B cells ensheath migrating neuroblasts. Type-B cells divide to generate by successive asymmetric or symmetric division TAPs (type-C cells).

Type-C cells represent the most important pool of proliferating progenitors within the SVZ, as type-2 cells in the DG. These cells are larger and more spherical than type-B cells and are intimately connected to blood vessels. Type-B cells form a tubular sheath surrounding type-C cells. Initial observations revealed that in vitro “neurospheres” were derived from type-B NSCs (Doetsch et al. 2002), however, a new study indicates that this neurosphere-forming ability is also an intrinsic property of type-C cells (Pastrana et al. 2009). In vivo, these cells still lack a specific clear-cut molecular marker that differentiate them from other cells (Doetsch et al. 1999). It was reported recently that type-C cells express specifically transcription factor Mash1 and a homeobox transcription factor, Distal less 2 (Dlx2), which is also express in type-A cells (Ming and Song 2011). Type-C cells will give rise to neuroblasts also named type-A cells.

The ultimate precursor type in the lineage progression of the adult SVZ is type-A cell. These cells express Dlx2 and are also characterized by the expression of proteins related to migration as DCX and PSA-NCAM (PolySialic Acid – Neuronal Cell Adhesion Molecule) – the embryonic form of NCAM. In the RMS, type-A cells form chains and migrate toward the OB through glial tube formed by astrocytes.

Six days after their birth in the SVZ, the first neuroblasts arrive in the OB and migrate radially into the layers where they differentiate into mature interneurons. A majority of neuroblasts differentiate into GABAergic granule neurons while a minority differentiate into GABAergic periglomerular neurons and a small portion into dopaminergic neurons. Finally, new granule cells with mature morphologies display spontaneous synaptic potentials (Carleton et al. 2003).

The cell cycle consists in a series of sequential phases that takes place in a cell leading to its division and replication. The duration of the cell cycle varies from 2 to 3 h in unicellular organisms (such as Saccharomyces cerevisiae) to 24 h in eukaryotic cells. In prokaryotic cells, which lack a nucleus, the cell cycle occurs through binary fission: circular DNA is replicated, and then the cell splits into two identical cells which contain an exact copy of the original DNA. In eukaryotic cells, the cell cycle is an elaborate replication process divided in two periods: interphase and mitosis (M). Interphase leads to DNA duplication and comprises three distinct phases: G1 (Gap 1), S phase (DNA synthesis) and G2 (Gap 2). During G1, the expression of genes required for G1 progression and S phase entry results mostly from the initial Rb phosphorylation. After DNA replication that occurs in S phase, the cell enters in G2 where significant proteic biosynthesis occurs, mainly involving in the generation of microtubules necessary for mitosis. The process of mitosis comprises five phases: prophase, metaphase, anaphase, telophase and cytokinesis (a cytoplasmic division). Errors in mitosis often lead to cell cycle arrest and apoptotic cell death to avoid genomic instability and accumulation of mutations. Dependent of environmental and development signals, cells in G1 may stop their division and, temporarily or permanently, leave the cell cycle to enter in a quiescence or senescence state, i.e. G0 phase (Gap 0). During this stage, cells may remain quiescent for long periods of time (like skin fibroblasts or liver hepatic cells), possibly permanently (i.e. neurons or cardiac cells); or cells may enter in senescence in response to DNA damage or degradation.

The progress through the cell cycle requires the assembly of complexes of cyclin-dependent kinase (CDK, catalytic subunit) and a cyclin (regulator subunit) (Fig. 2.2). Functional heterodimer enters into the cell nucleus where it gets phosphorylated by a CDK-activating kinase (CAK) to activate or inhibit its target proteins and allows the entry into the next phase of the cell cycle. In mammals, they are at least 15 different cyclins known from Cyclin A to Cyclin Y, and 21 genes encoding CDKs among which a few (CDK1, CDK2, CDK4, CDK6) are exclusively associated with cell cycle regulation (Malumbres and Barbacid 2009). Each cyclin can bind one or two CDKs and each CDK can be associated with one or two cyclins. CDKs are constitutively expressed in cells whereas cyclins are synthesized in a cyclic manner in response to various molecular signals at specific cell cycle stages.

When quiescent cells (G0) enter into the cell cycle (in G1), the D-type cyclins (i.e. cyclin D1, D2 and D3) are expressed in response to mitogenic signals and bind to their catalytic partners, CDK4 or CDK6. The kinase activity of these complexes results in the expression of genes whose products are involved in G1/S transition and S phase progression. The G1/S transition requires the binding of CDK2 to cyclin E. CDK2 activity is also implicated in S phase progression through binding with cyclin A. Cyclin A is also important for G2/M transition through its association with CDK1. Finally, during M phase, cyclin B/CDK1 phosphorylates several important structural components of the cell that are responsible for nuclear envelope breakdown and reorganization of the microtubule and actin filaments.

Redundancy exists between cyclins: in the absence of cyclin E-Cdk2, cyclin A-Cdk2 can promote G1/S transition while cyclin D-CDK4/6 and cyclin E-CDK2 play redundant roles during G1/S progression. The degradation of cyclins A and B is regulated by the APC/C complex (Anaphase-Promoting Complex/Cyclosome) and the APC/C inhibitor Emi1 (Early Mitotic Inhibitor 1). The APC/C complex is an ubiquitin multisubunit E3 ligase, which contribute to the degradation of cyclins A and B by promoting poly-ubiquitinylation. Expression of these cyclins in S phase and G2 requires the inactivation of APC/C by Emi1 whose transcription is induced by E2F transcription factors. Emi1 is stabilized through binding to Evi5, while its degradation occurs after phosphorylation by Plk1 (Polo-like kinase 1).

The activity of CDKs is regulated by both activating and inhibitory phosphorylations due to their association with cyclins, but also with “non-cyclin” CDK activators or CDK inhibitors.