Notch Signaling, Brain Development, and Human Disease

0031-3998/05/5705-0104R PEDIATRIC RESEARCH Vol. 57, No. 5, Pt 2, 2005 Copyright © 2005 International Pediatric Research Foundation, Inc. Printed in U.S.A. Notch Signaling, Brain Development, and Human Disease JOSEPH L. LASKY AND HONG WU University of California, Los Angeles School of Medicine, Department of Molecular and Medical Pharmacology, Los Angeles, California, 90025 ABSTRACT The Notch signaling pathway is central to a wide array of summarizes what is currently known about the role of the Notch developmental processes in a number of organ systems, includ- pathway in neural stem cells, gliogenesis, learning and memory, ing hematopoiesis, somitogenesis, vasculogenesis, and neuro- and neurologic disease. (Pediatr Res 57: 104R–109R, 2005) genesis. These processes involve maintenance of stem cell self- renewal, proliferation, specification of cell fate or differentiation, Abbreviations and apoptosis. Recent studies have led to the recognition of the FCD, focal cortical dysplasia role of the Notch pathway in early neurodevelopment, learning, ICD, intracellular domain and memory, as well as late-life neurodegeneration. This review PS1, presenilin1 The formation of the mammalian nervous system takes place interacts with Notch ligands, such as Delta or Serrate (in via a number of developmental steps. All phases of brain Drosophila), on an adjacent cell (Fig. 1). This interaction development involve the recurrent themes of induction, cell triggers two proteolytic events culminating in the release of the proliferation, cell fate determination (differentiation), cell Notch ICD. The free intracellular fragment then translocates to movement (migration), cell process formation, and targeting the nucleus where it binds to the transcriptional regulator CSL (synapse formation) (1). Signaling pathways involved in these [for CBF-1, Su(H), and LAG-1], resulting in displacement of processes are regulated not only in space, but in time and co-repressors previously bound to CSL and recruitment of intensity as well. A vast array of signaling events are coordi- co-activators. The co-activators then induce expression of the nated such that cells proliferate and differentiate at the correct Hairy-Enhancer of Split (HES) and Hes-related proteins time, space, and orientation to generate an amazingly orga- (HERP) gene families, although recent data suggest that CSL- nized structure capable of adaptability and plasticity. The independent pathways may also exist (2–4). It is also important Notch signaling pathway, originally discovered in Drosophila, to note that in mammals there exist multiple subtypes of each impinges on a wide array of cellular processes including “actor” in this pathway including Notch1–4, Delta-like ligands maintenance of stem cell self-renewal, proliferation, specifica- (Dll)-1,-3, and -4, and Serrate-like ligands (Jagged-1 and -2) tion of cell fate or differentiation, and apoptosis. What follows (3). This becomes relevant later on in this review in that is a review of the role of the Notch signaling pathway in various human diseases are usually associated with a particular neurodevelopmental processes and its role in the pathogenesis Notch gene. Notch is involved in mediating two distinct types of certain human neurologic diseases. of cell-cell signaling interactions: lateral and inductive signaling (5,6). Studies in Drosophila revealed the importance of DISCUSSION Notch in the control of cellular differentiation by lateral inhi- Notch signaling. The Notch gene encodes a receptor with a bition, which ensures that two distinct cell types are produced single transmembrane domain. Although initially synthesized in correct numbers from a population of initially equipotent as a single protein, it is cleaved in two and exists as a cells (7). For example, in Drosophila, Delta signaling to Notch heterodimeric receptor embedded in the plasma membrane. induces the Notch responding cell to remain a progenitor cell, Signaling is initiated when a Notch receptor on one cell whereas the Delta-expressing cell differentiates into a neural cell (8). Although the equipotent cells initially express equiv- Received January 4, 2005; accepted January 31, 2005. alent levels of both ligands and receptors, via a negative Correspondence: Joseph L. Lasky, M.D., Department of Molecular and Medical feedback mechanism, the Notch responding cell down- Pharmacology, UCLA School of Medicine, 650 Charles Young, Dr, 23-234 CHS, P.O. Box 951735, Los Angeles, CA 90095-1735; E-mail: [email protected] regulates its own Delta ligand expression effectively blocking Supported in part by NCI Cancer Education Grant R25 CA 098010. Notch receptor pathway activity in the Delta signaling cell 104R NOTCH, BRAIN DEVELOPMENT, AND DISEASE 105R Figure 1. The heterodimeric Notch receptor, upon contact with its ligand (e.g. Delta) undergoes proteolytic cleavage first by an ADAM family protease and then by ␥-secretase/presenilin1. This liberates the intracellular domain of Notch (ICD) allowing it to translocate into the nucleus where it displaces co-repressors (CoR) from the CSL transcription factor. Subsequent binding to CSL then occurs and recruitment of co-activators (CoA) results in the transcriptional activation of downstream target genes. (Fig. 2A). Inductive signaling, on the other hand, involves Notch receptor and ligand expressed on two different cell types such that Notch is only activated in the receptor-bearing cell, resulting in a cell-fate decision (Fig. 2B). This role for Notch signaling has been demonstrated in multiple settings including T-cell lineage specification (9,10), mammalian keratinocyte differentiation (11), and mammalian gliogenesis (12–14). The importance of these mechanisms is illustrated by their conser- vation across multiple species, from Drosophila and Caeno- rhabditis elegans to amphibians and mice (8,15–18). Stem cell maintenance. In Drosophila, Notch prevents early Figure 2. (A) Model of lateral inhibition: Two initially equipotent cells express equal levels of the Notch receptor and Delta ligand. If levels of a neurocompetence in ectodermal cells via interplay with the “proneural” fluctuate so as to increase in the cell on the right, Delta ligand Wnt signaling pathway (19,20). Although this particular role expression increases and Notch decreases in that cell, and neural differentiation has not yet been shown to be active in vertebrates, other commences. Secondary to increased Delta ligand exposure, an opposite pattern Notch1-mediated signaling pathways are crucial for mamma- in the left cell results such that Delta ligand expression is down-regulated and lian CNS development via maintenance of a neural stem cell Notch signaling predominates resulting in maintenance of an uncommitted progenitor state. (B) Example of inductive signaling: A neural stem cell (progenitor) state, inhibition of neuronal commitment, and expressing the Notch receptor may interact with a variety of cells depending on promotion of glial fates (12,21). Notch1 mouse mutant em- its environmental context. In this figure, for example, the Notch expressing cell bryos die before E11.5, near to the time when the first neurons may come into contact with an already committed neurogenic precursor express their mature, differentiated phenotype (17). However, expressing the Delta ligand. This contact initiates a cascade of signaling events close examination of mutant embryos revealed hypoplastic that, along with other cell extrinsic signals, results in glial fate commitment even in the setting of a strong pro-neurogenic signal such as BMP2 (14). In the brains and neural tubes secondary to a loss of neuroblasts and absence of this cell contact, the neural progenitor is instructed toward neuronal premature neuronal differentiation (22). Further support for the development. role of the Notch pathway in the inhibition of neuronal differentiation came from studies on PS1 (presenilin), which is a component of the ␥-secretase complex that allows for the for Notch signaling (12). In Hes1/Hes5 double mutant mice, efficient proteolytic release of the Notch ICD. PS1 knock-out virtually all the neural stem cells differentiate prematurely into mice (PS1Ϫ/Ϫ) also experience a reduction in the neural neurons resulting in severely disorganized neural tube mor- progenitor population (23). Consistent with these findings, phology and absence of development of normal brain struc- overexpression of Notch also promotes maintenance of neural tures (25). However, initial stem cell generation seems inde- precursors (13,24). The downstream signaling pathways re- pendent of Notch signaling (26). Recently, two forms of the sponsible for these effects are being elucidated. The basic mammalian neural stem cell have been proposed: the “primi- helix-loop-helix genes Hes1 and Hes5 are the major effectors tive” neural stem cell, isolated from E5.5 to E7.5 mouse 106R LASKY AND WU embryos that possess self-renewal capacity and neural multi- in postnatal developmental processes. Interest in Notch with potentiality, but also contain some non-neural properties (27); regards to plasticity and other higher brain functioning began and the “definitive” neural stem cell, which, generally isolated with its link to the presenilins that were initially discovered initially at E8.5, are FGF2 responsive (28). Notch1 appears to during early research on the genetic basis of Alzheimer’s be required for the transition from the primitive neural stem disease, which will not be further discussed, given excellent cell to the definitive

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