Not(ch) just development: Notch signalling in the adult brain

Abstract

The Notch pathway is often regarded as a developmental pathway, but components of Notch signalling are expressed and active in the adult brain. With the advent of more sophisticated genetic manipulations, evidence has emerged that suggests both conserved and novel roles for Notch signalling in the adult brain. Not surprisingly, Notch is a key regulator of adult neural stem cells, but it is increasingly clear that Notch signalling also has roles in the regulation of migration, morphology, synaptic plasticity and survival of immature and mature neurons. Understanding the many functions of Notch signalling in the adult brain, and its dysfunction in neurodegenerative disease and malignancy, is crucial to the development of new therapeutics that are centred around this pathway.

Figure 1. Notch signal transduction

A model of canonical Notch signalling. Notch signalling is unidirectional, with a ‘signal-sending cell’ that presents the Notch ligand (the ‘signal‘) to the ‘signal-receiving cell’, which expresses the Notch receptor. a | Notch ligands, such as Delta-like protein 1 (DLL1; shown in green), are presented on the neuronal membrane and subsequently endocytosed. These ligands can be ‘activated’ by an as-yet-unknown mechanism and re-presented to the membrane. b | Notch is synthesized as a single peptide and then cleaved in the golgi compartment (not shown) to form a heterodimer (shown in dark and light blue) that is presented on the cell membrane. c | Upon being re-established on the membrane, the ligand can bind Notch. d | According to one model, the Notch heterodimer is pulled apart through the force of endocytosis in the signal-sending cell, thereby transendocytosing the Notch extracellular domain (NECD). e | The Notch domain that remains on the signal-receiving cell is cleaved by disintegrin and metalloproteinase domain-containing protein (ADAM) and subsequently by γ-secretase. The precise location of the γ-secretase cleavage is controversial, with some data indicating that it occurs in the endosome and other data indicating that it can happen both on the membrane and in the endosome, leading to different Notch intracellular domain (NICD) molecules. f | In either case, after cleavage NICD translocates to the nucleus. g | In the nucleus it dislodges the repressor complex from recombining binding protein suppressor of hairless (RBPJ), forming a complex that is stabilized by mastermind-like protein (MAMLs). NICD also recruits co-activators to initiate transcription of Notch target genes. h | More recently, it has been determined that Notch signalling can occur in the absence of transcriptional activation, through protein–protein interactions, or that it can activate non-RBPJ-dependent transcription (not shown), collectively referred to as ‘non-canonical’ signalling.

Figure 2. Pleiotropic roles for Notch signalling in the adult brain

a | The generation of neurons in the adult brain is thought to proceed through several stages, beginning with radial glial-like neural stem cells (top left part) and ending in a mature neuron (bottom part). Early in the development of adult-born neurons, cells proceed through several divisions (shown by solid black arrows). Notch activation (N) occurs during, or immediately after, these divisions. Notch activation can also occur in postmitotic or quiescent cells in the absence of division (shown by dashed arrows). In radial glial-like stem cells (RGCs) Notch promotes a radial glial fate. In both RGCs and horizontal neural stem cells (NSCs), Notch activation promotes self-renewing divisions. Notch has also been implicated in regulating quiescence of NSCs. In progenitors, Notch activation is important for proliferation. Interestingly, in the subventricular zone, pigment epithelium-derived factor (PEDF) can sensitize progenitors such that low-level activation of Notch immediately following division can promote de-differentiation (that is, induce ‘stemness’). In its most well-known role, Notch inhibits neuronal differentiation of NSCs and progenitors. More recently, it has been appreciated that Notch regulates migration of neuroblasts and arborization of postmitotic newborn neurons. Notch has also been implicated in regulating synaptic plasticity of mature neurons (bottom right part) in the adult brain, regulating features of synaptic strengthening such as long-term potentiation (LTP) and long-term depression (LTD), and increases in the density of filopodia and spines. Finally, Notch is crucial for the survival of all stages of neurogenesis in both the developing and adult brain, either promoting or inhibiting apoptosis, depending on the stage. b | Following brain injury or degeneration, the developmental programs of Notch are reactivated to control a diverse set of responses to the insult, including promoting neuronal atrophy and death, increasing microglial activation, and potentially regulating reactive gliosis by initiating proliferation and astrogliogenesis from resident progenitors. However, the response is counter-productive and Notch activation limits the ability of oligodendrocytes to differentiate and remyelinate damaged neurons.

Figure 3. Notch integrates signals to coordinate a context-specific response

It is generally accepted that Notch signalling integrates multiple pathways, thereby tuning downstream expression to match the cell’s current needs and situation. This could be considered to resemble a processor on a circuit board, integrating inputs from various computing processes and directing output to appropriate hardware to generate a coordinated response. a | A representative sample of the various ‘inputs’, which include Notch ligands and input through crosstalking pathways, is shown (top part). The ability of a cell to receive input is regulated by the availability of the Notch receptor (not shown) and ligands, and by post-translational modification of both the receptor and ligands by fringe family proteins — such modification results in some Notch ligands being activating and others inhibiting. Input capacity is further modulated by intracellular ‘accessory pathway’ components and cofactors, such as deltex, neuralized (NEUR) and mastermind-like proteins (MAMLs), and extracellular inhibitors, all of which can bias Notch activation in one cell of the signalling pair. The output of Notch signalling (a representative sample of the currently identified ‘outputs’ is shown; bottom part) results from both canonical Notch signalling (activation of genes whose expression is regulated by recombining binding protein suppressor of hairless (RBPJ)-dependent Notch signalling) and presumably non-canonical Notch signalling mechanisms. However, data on non-canonical signalling are limited. The output depends in part on the Notch pathways that are available in a given cell type and in part on the combination of inputs. b | In neural stem cells (NSCs), for example, Notch integrates growth factor (epidermal growth factor receptor (EGFR) and pigment epithelium-derived factor (PEDF)) signalling with input from key stem pathways, such as sonic hedgehog (SHH) and WNT, to promote expression of genes that maintain stemness and self-renewal. c | In mature neurons, in which SHH has a less prominent role, Notch may integrate WNT, neurotrophin and NF-κB signalling to modulate synaptic complexity and survival. Most of the input and key pathways that interact with Notch in mature neurons are unknown (shown by dashed lines), as are the downstream effectors. Probable candidates include neurotrophins (for example, brain-derived neurotrophic factor (BDNF)), activity-dependent modulators of synaptic and structural plasticity (for example, NF-κB), as well as effectors of cytoskeletal rearrangement (for example, RAS-related C3 botulinum toxin (RAC) proteins and β-catenin). Inputs that inhibit Notch signalling are shown in purple, and inputs that potentiate Notch signalling are shown in yellow. Inputs and outputs that play a less prominent part in a given stage are shown in grey with open circles. ADAM, a disintegrin and metalloproteinase domain-containing protein; AKT, serine/threonine-protein kinase AKT; BLBP, fatty acid-binding protein, brain; CDK2, cyclin-dependent kinase 2; DLL, Delta-like protein; DNER, Delta and Notch-like epidermal growth factor-related receptor; DLK, protein delta homologue 1; EGFL7, epidermal growth factor-like protein 7; FBW7, F-box/WD repeat-containing protein 7; HESR, hairy and enhancer of split-related genes; HIF1α, hypoxia-inducible factor 1A; IGFR, insulin-like growth factor receptor; mTOR, mammalian target of rapamycin; STAT3, signal transducer and activator of transcription 3.