In recent years a large number of studies have investigated the role of NTs in adult neurogenesis, identifying both expected and unexpected functions for this protein family of ligands and their receptors. A recurrent theme has been the prominent role of BDNF/TrkB in dendrite and spine morphogenesis, both in the OB and the dentate gyrus. Furthermore, p75NTR has been linked to progenitor proliferation and migration in the SVZ-RMS and to axon initiation in the SGZ. NT3 appears to play a very early role in the SVZ as a modulator of NSC quiescence and a late role in the dentate gyrus, where it likely regulates maturation/survival of newly generated neurons. Despite these advances, several key questions remain unanswered. For instance, the function of pro-neurotrophins and their regulation by external stimuli has been scarcely addressed. Cross-talk between NTs and other niche factors also remains largely unexplored. More studies are clearly needed to fully understand the signaling pathways operating downstream of NTs and their receptors, and to determine whether or not these pathways are altered in pathological processes. We anticipate that future research will add to and further refine current knowledge, and possibly uncover additional functions for neurotrophins in adult neurogenesis, both in health and disease.
Neurotrophins (NTs) are implicated in the maintenance and survival of the peripheral and central nervous systems and mediate several forms of synaptic plasticity (Chao, 2003; Ceni et al., 2014; Hempstead, 2014; Lu et al., 2014). Nerve growth factor (NGF) was the first discovered member of the family (Cohen et al., 1954), which also includes brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), and neurotrophin 4/5 (NT4/5) (reviewed recently in Bothwell, 2014). Neurotrophins were first identified as survival factors for developing neurons, but are pleiotropic molecules that can exert a variety of functions, including the regulation of neuronal differentiation, axonal and dendritic growth, and synaptic plasticity (Bothwell, 2014).
NTs interact with two distinct receptors, a cognate member of the Trk receptor tyrosine kinase family and the common p75 neurotrophin receptor (p75NTR), which belongs to the tumor necrosis factor receptor (TNFR) superfamily of death receptors (Friedman and Greene, 1999; Huang and Reichardt, 2003). Tropomyosin receptor kinase (Trk) receptors belong to the family of receptor tyrosine kinases (reviewed in Deinhardt and Chao, 2014) and contain an extracellular domain at which the NT binds, a single transmembrane domain, and an intracellular domain (ICD) with tyrosine kinase activity. Three different Trks have been identified in mammals: TrkA, TrkB, and TrkC. NGF is the preferred ligand for TrkA, BDNF, and NT4/5 are preferred for TrkB, and NT3 for TrkC. These specificities are not absolute, and NT3 is also a ligand for TrkA and TrkB. In addition to full length (FL) receptors, splice variants containing either deletions in the extracellular domain or intracellular truncations including the kinase domain have been described. These receptor molecules may influence ligand specificity, restrict its availability by internalization, or act as dominant-negative modulators. Splice variants of TrkB, designated T1 and T2, are expressed at high levels in the mature brain (Klein et al., 1990).
While Trk receptors bind only to mature neurotrophins, p75NTR also interacts with pro-neurotrophins, increasing the complexity of its signaling. Upon pro-NGF binding, cell death is induced by a complex consisting of p75NTR and sortilin (Hempstead, 2014). Similarly, pro-BDNF induces axon pruning of hippocampal neurons in culture (Hempstead, 2015). Although, Trk signaling is involved in survival and differentiation (Reichardt, 2006; Deinhardt and Chao, 2014), p75NTR participates in several signaling pathways (Kraemer et al., 2014) governed by the cell context and the formation of complexes with different co-receptors and ligands, such as sortilin/pro-NGF in cell death (Nykjaer et al., 2004) and Nogo/Lingo-1/NgR in axonal growth (Wang et al., 2002; Mi et al., 2004). p75NTR also undergoes shedding and receptor intramembrane proteolysis (RIP), resulting in the release of its ICD, which itself possesses signaling capabilities related to migration, proliferation, and transcriptional modulation (Jung et al., 2003; Kanning et al., 2003; Skeldal et al., 2012). Two different isoforms of p75NTR have been described, a long isoform and a short isoform (Naumann et al., 2002). These isoforms differ based on the presence or absence of the NT binding domain, respectively.
In recent years, NTs and their receptors have emerged as important regulators of adult neurogenesis. The production of new neurons persists throughout life in two regions or niches of the mammalian brain in which neurotrophins are also present: the subependymal or subventricular zone (SVZ) adjacent to the lateral ventricles, and the subgranular zone (SGZ) of the dentate gyrus in the hippocampal formation. Neurogenesis persists in these specialized areas owing to the existence of a population of neural stem cells (NSCs) that retain the capacity to proliferate and generate new neurons via a series of intermediate progenitor cells. NSCs can also give rise to glial cells. In both the SVZ and SGZ, these NSCs are largely regulated by local signals emanating from other niche cell types such as astrocytes or endothelial cells. In addition, SVZ-NSCs contact the ventricular lumen and are regulated by signals within the cerebral spinal fluid (CSF), and by signals released by ependymal cells. Neuroblasts and immature neurons born in the SVZ are exposed to signals from the rostral migratory stream (RMS) during their journey to the olfactory bulb (OB), where they terminally integrate.
Here, we review the current understanding of the role of neurotrophins and their receptors in the regulation of adult neurogenesis, as well as the underlying mechanisms. We discuss the main findings pertaining to the two main neurogenic niches of the adult brain, the SVZ and the SGZ. We also highlight unexpected findings that have expanded the traditional perspective of neurotrophin function.
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