Notch: from neural development to neurological disorders

Abstract

Notch is an integral membrane protein that functions as receptor for ligands such as jagged and delta that are associated with the surface of neighboring cells. Upon ligand binding, notch is proteolytically cleaved within its transmembrane domain by presenilin-1 (the enzymatic component of the gamma-secretase complex) resulting in the release of a notch intracellular domain which translocates to the nucleus where it regulates gene expression. Notch signaling plays multiple roles in the development of the CNS including regulating neural stem cell (NSC) proliferation, survival, self-renewal and differentiation. Notch is also present in post-mitotic neurons in the adult CNS wherein its activation influences structural and functional plasticity including processes involved in learning and memory. Recent findings suggest that notch signaling in neurons, glia, and NSCs may be involved in pathological changes that occur in disorders such as stroke, Alzheimer's disease and CNS tumors. Studies of animal models suggest the potential of agents that target notch signaling as therapeutic interventions for several different CNS disorders.

Figure 1

Roles of notch signaling in development and neurological disorders. The illustration depicts the canonical notch signaling pathway (center) and involvement in developmental processes (left) as well as adult neurological disorders (right). Neighboring cells possess the notch ligand (jagged or delta) and the target cell contains the notch receptor. Activation of notch upon ligand binding will release the notch intracellular domain (NICD) as a result of its cleavage by γ-secretase. NICD then translocates into the nucleus where it can interact with CSL and convert CSL from a transcriptional repressor to transcriptional activator. This conversion occurs by direct protein-protein interactions between NICD, SKIP and CSL, which leads to SMRT/HDAC dissociation. Notch/CSL recruit HATs to assist chromatin remodeling, and RBPJk and mastermind to activate specific targets. Notch signaling plays an important role during CNS development (left). During neural stem cell (NSC) divisions, numb is concentrated in the apical cell while notch is concentrated in the basal cell. NSC survival is promoted by notch-2, delta like ligand (Dll) 4, as well as numb and numblike. NSCs undergo precocious neuronal differentiation (blue cells) as a result of a compromised notch-1, presenilin (PS) 1 or 2, Dll1, RBPjκ, HES 1 or 2, numb, or numb like activity. In addition, a radial glia/NSC cell fate can be influenced by over-expression of either notch 1 or 3. Notch signaling has also been implicated in many adult neurological disorders (right). In synaptic plasticity, reduction in notch-1 signaling results in decreased long term potentiation (LTP) as well as reduction in learning and memory. Because mutations in presenilin-1/γ-secretase are linked to some inherited forms of Alzheimer’s disease, notch signaling has been proposed to play a role in this disease. In humans with mutations of notch-3, vascular development is impacted and leads to CADASIL a disorder characterized by cerebral vascular infarctions. In a mouse model of stoke, a reduction of notch 1 and/or γ-secretase leads to decreased activated microglia and inflammation, and improves functional outcome. Notch signaling in NSCs may enhance neurogenesis and functional recovery from a stroke. In CNS tumors, cancer stem cells express high levels of molecules in the notch signaling pathway (notch 1–3, delta, jagged 1, Hes 1, 2, 4), suggesting that modulation of notch signaling could be a potential therapeutic target to inhibit tumor progression.