Abstract
Photoreceptor cells are specialized neurons with a sensory cilium carrying an elaborate membrane structure, the outer segment (OS). Inherited mutations in genes involved in ciliogenesis frequently result in OS malformation and blindness. ADP-ribosylation factor-like 2 (ARL2) has recently been implicated in OS formation through its association with Binder of ARL2 (BART or ARL2BP), a protein linked to inherited blinding disease. To test the role of ARL2 in vision we created a transgenic mouse model expressing a tagged-dominant active form of human ARL2 (ARL2-Q70L) under a rod-specific promoter. Transgenic ARL2-Q70L animals exhibit reduced photoreceptor cell function as early as post-natal day 16 and progressive rod degeneration. We attribute loss of photoreceptor function to the defective OS morphogenesis in the ARL2-Q70L transgenic model. ARL2-Q70L expression results in shortened inner and outer segments, shortened and mislocalized axonemes and cytoplasmic accumulation of rhodopsin. In conclusion, we show that ARL2-Q70L is crucial for photoreceptor neuron sensory cilium development. Future research will expand upon our hypothesis that ARL2-Q70L mutant interferes with microtubule maintenance and tubulin regulation resulting in impaired growth of the axoneme and elaboration of the photoreceptor outer segment.
Highlights
The outer segment (OS) of photoreceptor neurons is a non-motile cilium that is specialized in light perception[1]
We have discovered a novel regulator of rod photoreceptor development and function, ADP-ribosylation factor-like 2 (ARL2)
Our first indication that ARL2 plays a role in OS morphogenesis was the endogenous mRNA expression profile, which demonstrates a “switch”-like spike in retinal message levels at approximately P9, a critical period of OS elaboration (Fig. 1A)
Summary
The outer segment (OS) of photoreceptor neurons is a non-motile cilium that is specialized in light perception[1]. A number of small GTPases, which act as molecular switches, are believed to play a role in regulating protein-protein interactions throughout the process of ciliogenesis and OS formation[1,4,5,6]. Studies of ARL2 and ARL3, a close ARL2 homolog, suggest that they may have overlapping functions They are thought to regulate trafficking of prenylated proteins through their interaction with prenyl binding protein δ (PrBPδ)[9,10]. ARL2 is localized at the centrosome in cell lines where it is proposed to act as a microtubule regulator in an ARL2BP-independent manner[14] These data suggest that ARL2 may play a role in OS formation by regulating tubulin or ARL2BP at photoreceptor cilium
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