Bachmann-Gagescu, R., Phelps, I.G., Stearns, G., Link, B.A., Brockerhoff, S.E., Moens, C.B., and Doherty, D. (2011) The Ciliopathy Gene cc2d2a controls Zebrafish Photoreceptor Outer Segment Development Through a Role in Rab8-dependent Vesicle Trafficking. Hum. Mol. Genet.. 20(20):4041-55.
Ciliopathies are a genetically and phenotypically heterogeneous group of human developmental disorders whose root cause is
the absence or dysfunction of primary cilia. Joubert syndrome is characterized by a distinctive hindbrain malformation variably
associated with retinal dystrophy and cystic kidney disease. Mutations in CC2D2A are found in <10% of patients with Joubert syndrome. Here we describe the retinal phenotype of cc2d2a mutant zebrafish consisting of disorganized rod and cone photoreceptor outer segments resulting in abnormal visual function
as measured by electroretinogram. Our analysis reveals trafficking defects in mutant photoreceptors affecting transmembrane
outer segment proteins (opsins) and striking accumulation of vesicles, suggesting a role for Cc2d2a in vesicle trafficking
and fusion. This is further supported by mislocalization of Rab8, a key regulator of opsin carrier vesicle trafficking, in
cc2d2a mutant photoreceptors and by enhancement of the cc2d2a retinal and kidney phenotypes with partial knockdown of rab8. We demonstrate that Cc2d2a localizes to the connecting cilium in photoreceptors and to the transition zone in other ciliated
cell types and that cilia are present in these cells in cc2d2a mutants, arguing against a primary function for Cc2d2a in ciliogenesis. Our data support a model where Cc2d2a, localized
at the photoreceptor connecting cilium/transition zone, facilitates protein transport through a role in Rab8-dependent vesicle
trafficking and fusion.