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Review
. 2012 Aug;22(4):339-46.
doi: 10.1016/j.gde.2012.04.003. Epub 2012 May 17.

Notch signaling and neural connectivity

Edward Giniger  1
Affiliations
Review

Notch signaling and neural connectivity

Edward Giniger. Curr Opin Genet Dev. 2012 Aug.

Abstract

The cell surface receptor Notch contributes to the development of nearly every tissue in most metazoans by controlling the fates and differentiation of cells. Recent results have now established that Notch also regulates the connectivity of the nervous system, and does so at a variety of levels, including specification of neuronal identity, division, survival and migration, as well as axon guidance, morphogenesis of dendritic arbors and weighting of synapse strength. To these ends, Notch engages at least two signal transduction pathways, one that controls nuclear gene expression and another that directly targets the cytoskeleton. Coordinating the many functions of Notch to produce neural structure is thus a pivotal aspect of building and maintaining the nervous system.

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Figures

Figure 1
Figure 1. Notch-regulated events in the development of neural connections
A and B represent two neurons with different identities and projection patterns. Green oblongs represent substratum cells for the axon of “B”, blue neuron represents a synaptic target of “B”, gray bars represent synapses.
Figure 2
Figure 2. Indirect and direct control of neuronal projections by Notch
A) Axon targeting as a feature of cell identity. Most olfactory sensillae in the Drosophila antenna include a pair of sibling neurons, one of which has active Notch signaling at birth (orange) and one that does not (cyan). These cells express different olfactory receptors and project to different glomeruli (lightly shaded oblongs) in the antennal lobe of the brain. Inactivating Notch signaling causes both neurons to project to the glomerulus appropriate for the Notch-OFF cell, activation of Notch causes both to project to the target of the Notch-ON cell. Olfactory receptor expression is switched in parallel with the projection pattern. (Unlike in vertebrates, the Drosophila olfactory receptor protein is not responsible for axon targeting.) Figure adapted from [14]. B) Direct modulation of dendritic branching. Mammalian cortical neurons growing at low or high cell density are depicted [23]. For clarity, one cell in each panel is shown in dark blue and axons are not shown. All of the cells express both Notch and a Notch ligand, allowing mutual activation of Notch when two cells come into contact. At low density, where there are initially few contacts between adjacent cells, Notch signaling is weak (light green nuclei) and the dendritic tree is sparse, with long branches. At high cell density, multiple contacts between dendrites of adjacent cells induce strong Notch signaling (dark green nuclei), and dendrites are short, and highly branched.
Figure 3
Figure 3. Notch signaling mechanisms
A) Canonical Notch signaling. After binding of Notch to its ligand (Delta or Serrate/Jagged), ligand endocytosis (1) exerts tension on the Notch extracellular domain, allowing sequential cleavage, first by (2) an ADAM metalloprotease (such as Kuzbanian), and then by (3) the γ-secretase complex. This frees the Notch intracellular domain (NICD) to translocate to the nucleus (4), where it forms a transcriptional activator complex, together with a DNA-binding unit (“CSL” protein: CBF1/RBP-Jκ; Suppressor of Hairless; Lag-1) and a coactivator (Mastermind). The complex binds promoters of target genes bearing CSL-binding sites (5) and stimulates their transcription. B) Notch/Abl cytoplasmic signaling. Notch binds to and suppresses the effects of two cofactors of Abl tyrosine kinase, the adaptor protein, Disabled and the Rac guanine exchange factor (GEF), Trio [36]. Disabled is an upstream regulator of Abl kinase and its target, Enabled [53], Trio is an upstream regulator of Rac GTPase [54]. Enabled and Rac, in turn, control actin structure and dynamics in the growth cone [25].
Figure 4
Figure 4. Two forms of Notch activity in CNS longitudinal axon growth in Drosophila
A) Notch plays two parallel, but separate, roles to promote growth of longitudinal axons in the Drosophila CNS [25]. Canonical, nuclear Notch signaling in glial cells (green) promotes morphogenesis of the substratum for approaching pioneer axons (dMP2, vMP2; black). “Non-canonical”, cytoplasmic Notch signaling in the growth cones of the pioneer axons drives their extension alongside the glia. Ligand for both Notch functions is provided by the axons of commissural interneurons that bear Delta protein (pink), and that cross the longitudinal pathway. It is likely that there is also some level of canonical Notch signaling occurring in the pioneer neurons (light gray nuclei). CNS midline is indicated to the right; Delta+ commissural interneurons are located laterally in the nerve cord (left).
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