The ciliopathy gene cc2d2a controls zebrafish photoreceptor outer segment development through a role in Rab8-dependent vesicle trafficking

Bachmann‐Gagescu, Ruxandra; Phelps, Ian G.; Stearns, George; Link, Brian A.; Brockerhoff, Susan E.; Moens, Cecilia B.; Doherty, Dan

doi:10.1093/hmg/ddr332

Cited by 112 publications

(127 citation statements)

References 81 publications

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“…All OS proteins are synthesized in the IS. Impaired transport of OS proteins from the IS to the basal body or insufficient supply of OS proteins will impede OS development, and finally lead to photoreceptor degeneration [4,29]. In Drosophila, rhodopsin normally colocalizes with Rab11 in vesicles, and the loss of Rab11 activity results in the accumulation of npg rhodopsin-containing vesicles in the cytoplasm [30].…”

Section: Mislocalization Of Os Proteins In Dlic1 −/− Photoreceptor Cellsmentioning

confidence: 99%

Dlic1 deficiency impairs ciliogenesis of photoreceptors by destabilizing dynein

Kong

Peng

et al. 2013

Cell Res

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Cytoplasmic dynein 1 is fundamentally important for transporting a variety of essential cargoes along microtubules within eukaryotic cells. However, in mammals, few mutants are available for studying the effects of defects in dynein-controlled processes in the context of the whole organism. Here, we deleted mouse Dlic1 gene encoding DLIC1, a subunit of the dynein complex. Dlic1 −/− mice are viable, but display severe photoreceptor degeneration. Ablation of Dlic1 results in ectopic accumulation of outer segment (OS) proteins, and impairs OS growth and ciliogenesis of photoreceptors by interfering with Rab11-vesicle trafficking and blocking efficient OS protein transport from Golgi to the basal body. Our studies show that Dlic1 deficiency partially blocks vesicle export from endoplasmic reticulum (ER), but seems not to affect vesicle transport from the ER to Golgi. Further mechanistic study reveals that lack of Dlic1 destabilizes dynein subunits and alters the normal subcellular distribution of dynein in photoreceptors, probably due to the impaired transport function of dynein. Our results demonstrate that Dlic1 plays important roles in ciliogenesis and protein transport to the OS, and is required for photoreceptor development and survival. The Dlic1 −/− mice also provide a new mouse model to study human retinal degeneration.

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Section: Mislocalization Of Os Proteins In Dlic1 −/− Photoreceptor Cellsmentioning

confidence: 99%

Dlic1 deficiency impairs ciliogenesis of photoreceptors by destabilizing dynein

Kong

Peng

et al. 2013

Cell Res

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“…Interestingly, Rab8 is involved in the development of Kupffer's vesicle in zebrafish (Nachury et al, 2007) and regulates vesicle trafficking in Xenopus photoreceptors (Moritz et al, 2001). Furthermore, knockdown of Rab8 in cc2d2a mutant zebrafish enhances pronephric cyst formation (Bachmann-Gagescu et al, 2011). Further studies are required to define whether Rab8 and septin 7 function together in the regulation of vesicle trafficking and, thereby, ciliogenesis in these tissues.…”

Section: Discussionmentioning

confidence: 99%

sept7b is essential for pronephric function and development of left–right asymmetry in zebrafish embryogenesis

Dash¹,

Lehtonen²,

Wasik³

et al. 2014

Development

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The conserved septin family of filamentous small GTPases plays important roles in mitosis, cell migration and cell morphogenesis by forming scaffolds and diffusion barriers. Recent studies in cultured cells in vitro indicate that a septin complex of septin 2, 7 and 9 is required for ciliogenesis and cilia function, but septin function in ciliogenesis in vertebrate organs in vivo is not understood. We show that sept7b is expressed in ciliated cells in different tissues during early zebrafish development. Knockdown of sept7b by using morpholino antisense oligonucleotides caused misorientation of basal bodies and cilia, reduction of apical actin and the shortening of motile cilia in Kupffer's vesicle and pronephric tubules. This resulted in pericardial and yolk sac edema, body axis curvature and hydrocephaly. Notably, in sept7b morphants we detected strong leftright asymmetry defects in the heart and lateral plate mesoderm (situs inversus), reduced fluid flow in the kidney, the formation of kidney cysts and loss of glomerular filtration barrier function. Thus, sept7b is essential during zebrafish development for pronephric function and ciliogenesis, and loss of expression of sept7b results in defects that resemble human ciliopathies.

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“…cc2d2a zebrafish morphants develop disorganized photoreceptor OS and accumulation of opsins and vesicles in IS. 43 Mutations in CC2D2A in humans lead to RP, often as part of multi-organ syndromes. [44][45][46] Growth of the microtubule axoneme is dependent on chaperone proteins such as prefoldin-5 that, when mutated in mice, leads to photoreceptor degeneration.…”

Section: Photoreceptor Development and Inherited Retinal Conditionsmentioning

confidence: 99%