Binary Function of ARL3-GTP Revealed by Gene Knockouts
UNC119 and PDEδ are lipid-binding proteins and are thought to form diffusible complexes with transducin-α and prenylated OS proteins, respectively, to mediate their trafficking to photoreceptor outer segments. Here, we investigate mechanisms of trafficking which are controlled by Arf-like protein 3 (Arl3), a small GTPase. The activity of ARL3 is regulated by a GEF (ARL13b) and a GAP (RP2). In a mouse germline knockout of RP2, ARL3-GTP is abundant as its intrinsic GTPase activity is extremely low. High levels of ARL3-GTP impair binding and trafficking of cargo to the outer segment. Germline knockout of ARL3 is embryonically lethal generating a syndromic ciliopathy-like phenotype. Retina- and rod-specific knockout of ARL3 allow to determine the precise mechanisms leading to photoreceptor degeneration. The knockouts reveal binary functions of ARL3-GTP as a key molecule in late-stage photoreceptor ciliogenesis and cargo displacement factor.
KeywordsARL3 ARL13b PDEδ UNC119 RP2 Photoreceptor Germline knockout Retina disease
This research was supported by a National Eye Institute grants EY08123, EY019298 (WB), EY014800-039003 (NEI core grant), unrestricted grants to the Departments of Ophthalmology at the University of Utah from Research to Prevent Blindness (RPB; New York), the Retina Research Foundation, Houston (Alice McPherson, MD), and the Foundation for Retina Research (David Brint, MD). WB is a recipient of a Research to Prevent Blindness Senior Investigator and Nelson Trust Award.