New Publication in eLife!!

The Pearring lab has a new publication out in eLife. This project was spear-headed by Amanda Travis, PhD a very talented postdoc in the lab. She was initially motivated by the need to understand the growing number of human mutations in Arl3 that present with dominant and recessive retinal dystrophy. Using in vivo models, she uncovered that expression of dominant human mutations disrupted rod nuclear migration during retinal development. She then used a variety of biochemical assays to uncover the effector binding behaviors of these mutants and found the two dominant mutations have different effects: one results in a fast cycling phenotype while the other causes constitutive activity. The importance of her work lays in the definitive discovery that dominant mutations cause a rod migration defect due to excess active Arl3 rather than a loss of function, which will be critical for distinguishing patient phenotypes and developing targeted therapeutics.

To understand how excessive Arl3 activity was causing the rod migration phenotype, Amanda went on to rescue the defect by overexpressing: (1) Arl3 effectors, (2) lipidated cargos bound for the cilium, (3) a mutant that eliminates all Arl3 activity, or (4) a mutant that restores ciliary activation of wild type Arl3. Together, these experiments show that the
driving force established by a Arl3-GTP ciliary gradient, similar to Ran-GTP in nuclear import, is critical for nuclear migration of rod photoreceptors. This novel link between ciliary function and rod nuclear migration will serve as an important foundation for future studies on the developmental migration of neurons.