The Lai Laboratory

Regulation of Notch Signaling for Cell Fate Control and Neural Morphogenesis.

Cellular signaling provides an important mechanism for cell specification and pattern formation during development. Our research focuses on two signal transduction pathways mediated by Notch and Receptor Tyrosine Kinase (RTK). RTK signaling plays an instructive role in cell fate decisions, whereas Notch signaling is often involved in restricting cellular competence for differentiation. Genetic analyses indicate that Notch and RTK signaling interact to specify cell fates, but underlying mechanism are not well understood. In our recent work, we show that Yan, and Ets transcriptional repressor that blocks cellular potential for specification and differentiation, is a target of Notch signaling during Drosophila eye development. Notch signaling is essential for establishing yan expression in the developing eye. In contrast, RTK signaling down-regulates yan expression by blocking an eye-specific yan enhancer. Thus, Notch signaling can be antagonized at the level of the enhancer by the RTK pathway.

Notch is a cell surface receptor that is activated through direct interaction with its ligand (e.g. Delta) produced by neighbor signal-sending cells. Interestingly, Delta can also act within signal-receiving cells to repress Notch signaling. We show that the Drosophila Leucine-Rich Repeat (LRR) transmembrane protein Gp150 is a modulator of Notch signaling. Gp150 is colocalized with Delta in intracellular vesicles, and loss of gp150 function causes accumulation of intracellular Delta protein. Thus, Gp150 might function in intracellular vesicles to modulate Notch signaling for cell fate control and neural morphogenesis. Further studies are needed to address how intracellular Delta trafficking can be involved in Notch regulation.

Four Notch receptors and a number of Notch ligands are found in humans. Disruption of Notch signaling is associated with several human diseases, such as T-cell acute lymphoblastic leukemia/lymphoma. Studies on regulation of Notch signaling would help us to understand not only the normal human development, but also the cause of Notch-associated human diseases.

A Model for Crosstalk between Notch and RTK Signaling Pathways

In this model, we propose that Notch signaling acts in undifferentiated cells to promote yan expression and that Su(H) is directly involved in this process. Both E(spl) and Yan can negatively regulate yan transcription, which provides an inhibitory feedback mechanism. Once inductive RTK signals are available to initiate cellular differentiation, the Ets domain protein Pnt blocks yan transcription, while activated MAP kinase targets the Yan protein for phosphorylation and degradation. Therefore, opposition between Notch and RTK signals can be mediated at the level of enhancer through action of nuclear factors such as Su(H) and Pnt.