IGF2 is highly expressed, as shown by in situ hybridization, in CP epithelial cells not only during development (Lehtinen et al., 2011) but also in adulthood (Bondy et al., 1992). Under physiological conditions IGF2 was the second highest expressed gene found in a microarray study of the adult CP (Marques et al., 2011); the other member of the insulin growth factor family, insulin-like growth factor 1 (IGF1), is also expressed by adult CP epithelial cells, but only modestly. While the CP is not the only contributor to the presence of IGF1 and IGF2 in the CSF during development (other sites are the meninges and the endothelial cells of the brain blood vessels) (Lehtinen et al., 2011) it is certainly well positioned to rapidly influence the SVZ by paracrine effects. Both IGF1 and IGF2 proliferative actions are signaled via the insulin-like growth factor type 1 receptor (IGFR1) (Weber et al., 1992). IGF2 was found to be highly associated with the primary cilium of cortical progenitor cells that projects directly toward the CSF, indicating that IGF signaling occurs via IGF1R located in the primary cilia (Lehtinen et al., 2011). In fact, ablation of IGFR1 expression solely in neural precursor cells resulted in impaired cortical formation, namely microcephaly (Kappeler et al., 2008), similarly to what was found in IGF2-null mice (Lehtinen et al., 2011). Noticeably, IGFR1 is present both in the apical portion of the developing cortical ventricular zone surface, and in the adult SVZ (Yan et al., 2006), which highlights the importance of CP-CSF derived IGF signaling. In turn, IGF1's role in adult neurogenesis has been extensively demonstrated for the dentate gyrus since IGF1 infusion into the hippocampus increases proliferation and neurogenesis (Anderson et al., 2002). Similarly, when infused into the ventricles, IGF1 promotes cell proliferation and neurogenesis in the adult hypothalamus (Pérez-Martín et al., 2010). Furthermore, IGF1 seems to promote the exit of neuroblasts from the adult SVZ and their migration toward the olfactory bulb (Hurtado-Chong et al., 2009). This mismatch in the role of IGF1 in the hippocampus and adult SVZ niches results not only from the differences in the cellular distribution pattern of IGFR1 in both regions (Anderson et al., 2002), but also from the interaction of the IGF1 signaling cascade with other signaling factors such as BDNF and VEGF (Llorens-Martín et al., 2009). Noteworthy is the fact that the action of IGF1 in the two principal adult niches might also be conditioned by its binding to insulin growth factor binding proteins that might inhibit or potentiate the action of IGF1.

Of interest, the adult CP also expresses (Marques et al., 2011) and secretes (Thouvenot et al., 2006) several other insulin growth factor related proteins, such as insulin growth factor binding proteins, insulin growth factor receptors and insulin growth factor binding protein-like 1 (Igfbpl1). Of notice, the latter, is a protein found enriched in adult neural stem cells when compared with parenchymal astrocytes obtained by fluorescence-activated cell sorting (FACS) of SVZ cells (Beckervordersandforth et al., 2010). As for insulin-like growth factor binding protein 2 (Igfbp2), which is very highly expressed by the adult CP (Marques et al., 2011), its ability to support the survival and cycling of hematopoietic stem cells has been recently shown (Huynh et al., 2011). Whether IGFBP2 has a similar effect in the neural progenitor cell population in the adult SVZ is still unknown.

Another important group of growth factors expressed by the adult CP (Marques et al., 2011) is the fibroblast growth factor (FGF) family and related proteins. Their involvement in several processes of brain development (neural stem cell induction, cell differentiation, brain regions patterning, and neuronal circuit assembly) has been extensively demonstrated (Guillemot and Zimmer, 2011). In fact, the embryonic brain has several sources of different FGF family members that contribute to the determination of brain regionalization; for example, the contribution of CSF-derived FGFs to embryonic brain development was shown for FGF2 since it promotes precursor proliferation in chick embryos (Martín et al., 2006). FGF8, potentially derived from the CP-CSF, has also been described to participate in the patterning of brain regions in the chick (Parada et al., 2005) and mouse embryos (Fukuchi-Shimogori and Grove, 2001).

As for the adult brain, FGF2 injected in the ventricles increased proliferation in the SVZ and neurogenesis in the olfactory bulb (Kuhn et al., 1997). Furthermore subcutaneously injected FGF2, in both early post-natal and in young rats, crossed the brain barriers and increased in the CSF while promoting proliferation in both the subgranular zone of the dentate gyrus and the SVZ (Wagner et al., 1999). The importance of FGF2 for neuronal proliferation is illustrated by the extensive use of FGF2 (also known as bFGF) as a mitogen in SVZ neurosphere assays (Pastrana et al., 2011).

While less is known for the role of other FGF family members in adult neurogenesis it is of notice that FGF family members, such as FGF3, FGF9 and FGF10, are expressed under basal physiological conditions in the adult CP (Marques et al., 2011). Interestingly, FGF10 participation in the maintenance of the neurogenic potential of the adult SVZ was already suggested (Hajihosseini et al., 2008). Thus, under particular conditions, alterations in the expression of FGFs and their secretion toward the CSF may impact in the SVZ population.

In vitro, when exposed to epidermal growth factor (EGF), adult SVZ derived cells form neurospheres that display multipotent and self-renewal properties (Pastrana et al., 2011). Although expressed in a relative small number of type B1 cells, EGF receptor (EGFR) expressing cells that form neurospheres in vitro are derived mainly from transit amplifying C cells (Doetsch et al., 2002). In vivo, it was shown that high levels of EGF administered by intracerebroventricular infusion impacts on the SVZ by increasing proliferation and generating progeny that occupies the surrounding brain parenchyma, and also diverts SVZ cells from the neuronal lineage to the oligodendrocytic lineage (Doetsch et al., 2002; Gonzalez-Perez et al., 2009). While it is believed (Doetsch et al., 2002) that the probable source of EGFR signaling occurs via transforming growth factor alpha (TGFa), given its expression in the CP (Seroogy et al., 1993; Marques et al., 2011), we cannot exclude that this signaling pathway occurs through EGF, also expressed by the CP (Marques et al., 2011). The relevance of TGFa/EGF for EGFR in this context is illustrated by the observation that the decreased proliferation in the SVZ displayed by the TGFa knockout mice can be corrected by supplementation with EGF (Tropepe et al., 1997). Interestingly, TGFa signaling via EGFR was also shown to influence the migratory properties of cells in the RMS (Kim et al., 2009) and of oligodendrocyte precursors derived from SVZ cells (Gonzalez-Perez and Quiñones-Hinojosa, 2010). In addition, a role for TGFa/EGFR signaling in promoting migration of cells derived from the SVZ was highlighted by TGFa infusion to the dopamine-depleted striatum of rodent models of Parkinson's disease (Cooper and Isacson, 2004; de Chevigny et al., 2008). Despite the interesting potential of the CP as a source of TGFa/EGF for the modulation of the SVZ its specific physiological contribution has never been demonstrated, which certainly deserves additional research.

PDGF signaling also occurs via the primary cilium and, interestingly, the PDGF signaling pathway modulates neural stem cells and affects lineage fate. For instance, in vitro experiments showed that PDGF increased neurosphere formation (Jackson et al., 2006). Whether SVZ GFAP-positive neural stem cells express the platelet derived growth factor receptor alpha polypeptide (PDGFRa) is disputable (Jackson et al., 2006; Chojnacki et al., 2011; Ihrie and Álvarez-Buylla, 2011), but infusion of PDGF into the ventricle is known to bolster proliferation in the SVZ (Jackson et al., 2006). The endogenous source of this ligand has not been determined (Ihrie and Álvarez-Buylla, 2011) but recently we found that the CP expresses several PDGFs mRNAs (Marques et al., 2011), with particular emphasis to PDGFa. Once again, the physiological significance of this expression and its influence over the SVZ neural stem cell niche remains to be established.

During the formation of the central nervous system, FGF signaling action is frequently aligned with and/or counteracted by signaling from BMPs, Shh and Wnt pathways. The result of this interaction, impacting on cell proliferation and cell fate, is dependent of the highly dynamic spatiotemporal variation in the expression of the various effector proteins (Guillemot and Zimmer, 2011).

The role of BMP, Shh, and Wnt proteins derived from the CP-CSF during development has been shown. For instance, Shh expression in the hindbrain CP is high and CSF Shh was demonstrated to be essential for cerebellar development by promoting proliferation of granule precursors (Huang et al., 2009, 2010). BMPs, that together with Wnt and FGF proteins, participate in cortical development (Shimogori et al., 2004), display a very dynamic presence in the CSF in an age dependent manner (Lehtinen et al., 2011).

In the adult SVZ, all these proteins participate in the regulation of the SVZ niche. Adult SVZ type B and C cells express both BMP2 and BMP4 and their respective receptors, and SVZ ependymal cells alter the activity of BMPs (Lim et al., 2000; Peretto et al., 2004). The CP origin of these ligands should also be considered since it expresses BMP1, BMP2, BMP4, BMP6 and BMP7 under basal physiological conditions (Marques et al., 2011). Noteworthy, the presence of some of these BMPs in the adult CSF was also recently confirmed (Lehtinen et al., 2011). Furthermore, growth differentiation factors 3 and 8 (Gdf3 and Gdf8), known to modulate BMP signaling, are also expressed by the adult CP (Marques et al., 2011) and are secreted toward the CSF (Lehtinen et al., 2011).

Shh and Wnts pathways are also active in the adult SVZ and were implicated in the formation, maintenance, proliferation and migration of adult neural stem cells. Shh is produced by ventral forebrain neurons that extend projections toward the SVZ, and persistent Shh signaling determines a specific neural progeny (Ihrie et al., 2011). Shh is also expressed by the CP (Marques et al., 2011) but its levels in the adult CSF have not been determined. As for Wnt, evidence exists that it may participate in the regulation of the adult SVZ population, namely enhancing Wnt signaling via beta-catenin in type C cells increases proliferation and results in a higher number of neurons in the olfactory bulb (Adachi et al., 2007). On the other hand, during embryonic development Wnt may rather play a role in maintaining the SVZ stem cell pool (Piccin and Morshead, 2011). Similarly to Shh and BMPs, several members (for instance Wnt5a, 5b, and 10b) of the Wnt family are expressed in the adult CP, and specifically secreted by CP epithelial cells, under basal conditions (Thouvenot et al., 2006; Marques et al., 2011).

One of the most interesting features of the Shh and Wnt signaling pathways is that they are modulated by the primary cilium (Louvi and Grove, 2011), making the cilia projected by type B1 cells toward the CSF a particularly well positioned route for CP derived “messages”.

Neuroblasts derived from the SVZ form a stream of moving cells that converge in the RMS; they are ensheated by a layer of astrocyte processes and use each other as guides in the migration process toward the olfactory bulb (Lledo et al., 2008). Several proteins from the group of classical axon guidance molecules were implicated not only in the regulation of the migration of neuroblasts, but also in the proliferation of type B cells. For instance, SVZ cells express the EphA and EphB receptors; the ligands for these receptors are the transmembrane molecules ephrins. The relevance of these molecules in the modulation of the SVZ was shown by the infusion of the EphB2 ligand in the lateral ventricles, which disrupted the migratory chain of neuroblasts and increased the proliferation of type B1 cells (Conover et al., 2000). Interestingly, a role for EphB2 signaling was suggested in the conversion of ependymal cells to astrocytes after lesion of the ventricular wall (Nomura et al., 2010). Also, it has recently been shown that ephrinB3-EphB3 signaling in the SVZ is transiently inhibited to allow the expansion and survival of neural progenitor cells upon traumatic brain injury (Theus et al., 2010). EphrinB3 is one of the ephrins expressed by the CP at very low levels under basal physiological conditions (Marques et al., 2011). While the fact that these molecules are attached to the membrane might diminish the relevance of their expression in the CP in the modulation of the SVZ neural progenitors, the data provided by infusion experiments (Conover et al., 2000) suggest that the cleavage and release of ephrins from the membrane of CP cells toward the CSF, under particular conditions, could influence the response of type B1 cells.

Semaphorins and slits are guidance molecules that, contrary to ephrins, are secreted factors, and hence exert their effects to a certain distance, in a paracrine fashion. Several semaphorin family members and slits 1, 2, and 3 are expressed (Marques et al., 2011) and secreted by the CP (Hu, 1999; Sawamoto et al., 2006). Semaphorin signaling is usually associated with endothelial cells (Tamagnone and Mazzone, 2011); semaphorin-3a and its respective receptor are highly expressed in the endothelial cells that are present along the RMS (Meléndez-Herrera et al., 2008), suggesting a role for semaphorin-3a in the migration of neuroblasts. Whether semaphorins specifically secreted by the CP influence the migration of neuroblasts toward the olfactory bulb has not been determined.

On the other hand, a role for slits specifically derived from the CP in the modulation of SVZ neural progenitors niche was clearly shown; for instance, slit 2 was shown to participate in the regulation of neuronal migration of neurons in the developing brain (Hu, 1999). Interestingly both the adult SVZ and the RMS express the receptors Robo2 and Robo3 through which slit1 and slit 2 exert their chemorepulsive activities (Nguyen-Ba-Charvet, 2004). Importantly, it was shown (Sawamoto et al., 2006) that ciliary beating from ependymal cells that line the wall of the brain ventricles contribute to the movement of the CSF, hence creating gradients of the chemorepelent slits secreted by the CP (Nguyen-Ba-Charvet, 2004; Marques et al., 2011) and thus contributing to the anterior migration of neuroblasts to the olfactory bulbs. Nevertheless, the role of slits in directing the migration of future olfactory bulb neurons goes behind the influence of the CP since type C and type A cells also express slit1 (Nguyen-Ba-Charvet, 2004), which seems to avoid the invasion of the RMS by astrocytic processes (Kaneko et al., 2010).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.