The objective of this research is to understand the development of the visual system and retina and, in particular, precursor cells specified to particular fates. To address these issues, the investigator proposes to study the regulation of the ERK, a central molecule in the machinery used by all cells to interpret developmental signals. The inactive form of ERK is a cytoplasmic protein, where it exists in association with its own specific activating kinase, MEK, and the cells' microtubule skeleton. Signals from many sources can cause MEK to activate ERK. These signals include those from tyrosine kinases and other receptors. The active form of ERK is called dp-ERK, which has been thought to move immediately to the cell nucleus where it can act on transcription factors to control gene expression. In the developing retina, ERK signaling is regulated by receptor tyrosine kinases that include the EGF receptor. This pathway allows extracellular signals (such as growth factors) to affect retinal cell development. The investigator has found that Drosophila dp-ERK does not immediately move to the nucleus. Instead it is held in the cytoplasm until it is released by signals from a second pathway controlled by the Notch receptor. Notch is known to act in local signaling between contacting cells, including those in the developing retina. Thus, the investigator proposes that these two pathways interact to control retinal cell fate in Drosophila. As both pathways are known to act also in vertebrate retinal development, this novel aspect of regulation may be general. The investigator proposes to study Notch-regulated ERK cytoplasmic hold (CH) in both Drosophila and rats.
The specific aims are focused on uncovering the biochemical mechanism by which this occurs.
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