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First published online February 18, 2004
doi: 10.1242/10.1242/dev.01074

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Notch signaling: control of cell communication and cell fate

Howard Hughes Medical Institute, 545 Life Sciences Addition, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3200, USA e-mail: lai{at}fruitfly.org

View larger version (25K): [in a new window]   Fig. 1. Basic operation of the Notch pathway. The key players are a Delta-type ligand, the receptor Notch and the CSL transcription factor (see Table 1). Delta and Notch are transmembrane proteins containing extracellular arrays of EGF repeats (depicted by rectangles). Activation of Notch by its ligand triggers two proteolytic cleavages of Notch (S2 and S3, see also Box 2). S3 cleavage releases the Notch intracellular domain (Notchintra), which translocates to the nucleus. Notchintra activates CSL. The CSL co-repressor complex is displaced by a co-activator complex containing Notchintra (Co-A, green icons), which mediates Notch target gene activation. In the absence of nuclear Notchintra, CSL associates with a co-repressor complex (Co-R, red icons), which actively represses the transcription of Notch target genes.

View larger version (65K): [in a new window]   Fig. 2. Inhibitory Notch signaling restricts cell fates. (A) A proposed dynamic of Notch signaling among a group of equipotent cells. Initially, cells that share a special cell fate potential (gray) both send and receive Notch signals, known as `mutual' inhibitory Notch signaling. Later, one cell commits to the specialized fate (black) and inhibits surrounding cells (white) from adopting this fate, a situation known as `lateral' inhibitory Notch signaling. (B) The failure of Notch signaling results in extra cells adopting the special cell fate, while excessive Notch signaling prevents the differentiation of these cells. (C,D) Notch signaling inhibits neurogenesis in the Drosophila embryo. (C) A wild-type embryo stained for the neural marker ELAV (red). (D) An embryo that completely lacks Su(H), the fly CSL transcription factor, displays a strong excess of neurons - the classic `neurogenic' phenotype. (E,F) Notch signaling inhibits neurogenesis in Xenopus (images courtesy of Elise Lamar). Staining for a neural form of tubulin (purple) reveals neuronal differentiation. (E) The lower half of this embryo expresses constitutively active Notchintra, which inhibits neuronal differentiation [compare the number of neurons in the bracketed region in wild type (top) with the starred region in the mutant tissue (bottom)]. (F) The lower half of this embryo expresses an inhibitor of the Notch co-activator complex (dominant negative form of Mastermind). This leads to a failure of Notch signaling and a strong neurogenic phenotype (star).

View larger version (71K): [in a new window]   Fig. 3. Notch signaling specifies cell fate and behavior. (A) A schematic of inductive Notch signaling, which typically occurs between non-equivalent cell populations. In this case, the blue cells signal to adjacent white cells to induce a new cell fate or change their behavior (black cells). (B) The failure of inductive Notch signaling results in the absence of this cell fate or behavior, whereas excessive Notch signaling has the reciprocal effect. (C-E) Notch signaling promotes Drosophila wing growth. (C) Wild-type adult wing. (D) Wing containing large Su(H) mutant clones in which loss of the CSL transcription factor causes notching (stars), owing to the failure to specify the wing margin during earlier development. (E) Wing containing clones of cells that misexpress Delta and that induce a large wing overgrowth (image courtesy of Jose F. de Celis). (F,G) Notch signaling is involved in the segmentation clock. Shown are stage 3S zebrafish embryos stained for the Notch ligand DeltaC (images courtesy of Clarissa Henry). (F) In a wild-type embryo, DeltaC oscillates in stripes (arrows) that correlate with the partitioning of somites. (G) An embryo in which the bHLH repressor-encoding Notch target genes her1 and her7 have been inhibited by injection of morpholinos. The oscillatory pattern of DeltaC expression is lost (bracket), and such embryos develop abnormal somites. (G,H) Notch signaling promotes germline proliferation. Shown are C. elegans gonads stained with DAPI (blue) to reveal nuclei (images courtesy of Tim Schedl). (H) In the wild-type gonad, mitotic nuclei are localized to the distal region, while the remainder of the gonad is meiotic and produces germ cells (oocytes). (I) A gain-of-function mutant in the GLP-1 receptor (Notch) shows a `tumorous' phenotype in which mitotic cells are found throughout the gonad and germ cells fail to differentiate.

View larger version (138K): [in a new window]   Fig. 4. Notch-mediated asymmetric cell divisions are influenced by localized determinants. (A) An asymmetric cell division in which one cell divides to give two daughters that adopt different fates; Notch signaling is `on' in the green cell and `off' in the red cell. Although both cells express Notch and Delta, signaling is directional because the red cell inherits determinants [such as Numb (red crescent in the mother cell)] that inhibit Notch signaling in that cell. (B) Crescents are centered on one end of the mitotic spindle and segregated into only one daughter cell. Here, a crescent of Partner of Numb-GFP is visualized along with the spindle, which is labeled with tau-GFP (image courtesy of Fabrice Roegiers). (C) The two exterior cells of a Drosophila mechanosensory bristle are produced by the lineage shown in A. The shaft cell (sh) activates Notch signaling in its sister, the socket cell (so); the shaft cell does not have activated Notch because it inherits Numb. Activation of Notch in both cells results in two sockets (D), whereas a failure to activate Notch in either cell results in two shafts (E) (images courtesy of Scott Barolo).