Major Research Areas
Developmental Biology
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Notch Signaling
Figure 1. A highly simplified model of Notch signaling. Neur and Mib are E3 ubiquitin ligases that activate DSL ligands. Interaction between the extracellular domains of DSL and Notch triggers cleavage and release of the Notch intracellular domain (Nintra).

Control of cell fate and behavior by Notch signaling

Notch signal transduction

Coordinated development requires that cells communicate with each other. This is made possible by molecular mechanisms of cell-cell signaling, by which cells can influence each other's fate and behavior.

A cell signaling mechanism of fundamental importance to animal development is the Notch pathway (Figure 1).

It may be safely said that Notch signaling is required, in some reasonably direct fashion, for the development of most tissues in all animal species. As such, misregulation of Notch signaling underlies a variety of human diseases and cancers.

Many ways to use a pathway

We focus on a few developmental settings that are paradigms of Notch-regulated events. One broad category is "inhibitory" signaling, whereby Notch prevents a cell from adopting a particular cell fate, usually through the repression of celltype-specific determinants. For example, Notch signaling singles out individual neural precursors from clusters of cells with neural potential.

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Notch Signaling
Figure 2: Loss of Notch signaling results in ectopic sensory organs (due to failure of inhibitory signaling during neural restriction), and in loss of wing tissue (due to failure of inductive signaling during wing margin specification).

Loss of Notch signaling therefore causes excess neural differentiation (Figure 2, top). A second broad category is "inductive" signaling, whereby activation of Notch induces the expression of molecules with tissue-organizing activity.

For instance, Notch signaling specifies the wing margin, a line of cells that organizes the patterning and outgrowth of the wing proper. Loss of Notch signaling here results in loss of wing tissue (Figure 2, bottom).

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Figure 3
Figure 3: The ubiquitin ligase D-mib induces endocytosis of Delta (in red), a prerequisite for activation of Delta signaling activity.

Ubiquitin ligases activate DSL ligands and Notch signaling

We previously characterized two ubiquitin ligases, Neuralized and D-Mindbomb, which are absolutely required for inhibitory and inductive Notch signaling in flies, respectively. These unrelated ubiquitin ligases have a common ability to ubiquitinate both fly DSL ligands, Delta and Serrate. This modification induces DSL ligand endocytosis (Figure 3) and activates DSL signaling capacity. We are continuing to study how these ubiquitin ligases recognize DSL ligands, and how ligand endocytosis activates DSL signaling. We are also studying the regulation of these regulators, including their transcriptional and post-translational control. In particular, deployment of neuralized is highly spatially regulated. We have defined minimal enhancers that direct various aspects of neuralized transcription, and seek to define the trans-acting factors that control these enhancers.
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