Insights into photoreceptor ciliogenesis revealed by animal models

Baehr, Wolfgang; Hanke-Gogokhia, Christin; Sharif, Ali Sakawa; Reed, Michelle; Dahl, Tiffanie; Frederick, Jeanne M.; Ying, Guoxin

doi:10.1016/j.preteyeres.2018.12.004

Cited by 42 publications

(34 citation statements)

References 397 publications

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“…In the three decades since the genes linked to PR loss phenotype were first identified in the mouse and human [10][11][12], rapid progress in understanding the genetic basis of inherited RD has been summarized in many excellent reviews. Many of the topics presented in the current article have been discussed previously in reviews of mouse RD models [6,7,13,14] and in summaries of our work at JAX [15][16][17][18][19][20][21]. Although we have made every effort to acknowledge the many contributions to this field, we note that there is a large body of relevant literature and apologize in advance to authors whose reviews or articles we may have inadvertently overlooked.…”

Section: Introductionmentioning

confidence: 98%

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Collin

Gogna

Chang

et al. 2020

Cells

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Inherited retinal degeneration (RD) leads to the impairment or loss of vision in millions of individuals worldwide, most frequently due to the loss of photoreceptor (PR) cells. Animal models, particularly the laboratory mouse, have been used to understand the pathogenic mechanisms that underlie PR cell loss and to explore therapies that may prevent, delay, or reverse RD. Here, we reviewed entries in the Mouse Genome Informatics and PubMed databases to compile a comprehensive list of monogenic mouse models in which PR cell loss is demonstrated. The progression of PR cell loss with postnatal age was documented in mutant alleles of genes grouped by biological function. As anticipated, a wide range in the onset and rate of cell loss was observed among the reported models. The analysis underscored relationships between RD genes and ciliary function, transcription-coupled DNA damage repair, and cellular chloride homeostasis. Comparing the mouse gene list to human RD genes identified in the RetNet database revealed that mouse models are available for 40% of the known human diseases, suggesting opportunities for future research. This work may provide insight into the molecular players and pathways through which PR degenerative disease occurs and may be useful for planning translational studies.

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Section: Introductionmentioning

confidence: 98%

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Collin

Gogna

Chang

et al. 2020

Cells

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“…At the same time, proteins that are not authorized to pass the connecting cilium (in either direction) should be kept in their designated compartments. Several proteins at the connecting cilium are thought to organize a gate to control protein movement between the inner and the outer segments (3).…”

mentioning

confidence: 99%

The myosin-tail homology domain of centrosomal protein 290 is essential for protein confinement between the inner and outer segments in photoreceptors

Datta

Hendrickson

Brendalen

et al. 2019

Journal of Biological Chemistry

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Mutations in the centrosomal protein 290 (CEP290) gene cause various ciliopathies involving retinal degeneration. CEP290 proteins localize to the ciliary transition zone and are thought to act as a gatekeeper that controls ciliary protein trafficking. However, precise roles of CEP290 in photoreceptors and pathomechanisms of retinal degeneration in CEP290-associated ciliopathies are not sufficiently understood. Using conditional Cep290 mutant mice, in which the C-terminal myosin-tail homology domain of CEP290 is disrupted after the connecting cilium is assembled, we show that this domain is essential for protein confinement between the inner and the outer segments. Upon disruption of the myosin-tail homology domain, inner segment plasma membrane proteins, including syntaxin 3 (STX3), synaptosome-associated protein 25 (SNAP25), and interphotoreceptor matrix proteoglycan 2 (IMPG2), rapidly accumulated in the outer segment. In contrast, localization of endomembrane proteins was not altered. Trafficking and confinement of most outer segment-resident proteins appeared to be unaffected or only minimally affected in Cep290 mutant mice. One notable exception was rhodopsin (RHO), which severely mislocalized to inner segments during the initial stage of degeneration. Similar mislocalization phenotypes were observed in Cep290 rd16 mice. These results suggest that a failure of protein confinement at the connecting cilium and consequent accumulation of inner segment membrane proteins in the outer segment, along with insufficient RHO delivery, is part of the disease mechanisms that cause retinal degeneration in CEP290-associated ciliopathies. Our study provides insights into the pathomechanisms of retinal degenerations associated with compromised ciliary gates.

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“…It would also be interesting to use nonradioactive methods of phosphoinositide detection to compare the phosphoinositide composition of mouse and human retinas. Another future goal is to address whether pathological changes in the levels and distribution of phosphoinositides contribute to blindness in diseases that are not directly caused by disruptions of phosphoinositide metabolism, such as retinitis pigmentosa or syndromic ciliopathies [ 47 , 48 , 49 , 50 , 51 , 52 ].…”

Section: Discussionmentioning

confidence: 99%

Phosphoinositide Profile of the Mouse Retina

Finkelstein

Gospe

Schuhmann

et al. 2020

Cells

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Phosphoinositides are known to play multiple roles in eukaryotic cells. Although dysregulation of phosphoinositide metabolism in the retina has been reported to cause visual dysfunction in animal models and human patients, our understanding of the phosphoinositide composition of the retina is limited. Here, we report a characterization of the phosphoinositide profile of the mouse retina and an analysis of the subcellular localization of major phosphorylated phosphoinositide forms in light-sensitive photoreceptor neurons. Using chromatography of deacylated phosphatidylinositol headgroups, we established PI(4,5)P2 and PI(4)P as two major phosphorylated phosphoinositides in the retina. Using high-resolution mass spectrometry, we revealed 18:0/20:4 and 16:0/20:4 as major fatty-acyl chains of retinal phosphoinositides. Finally, analysis of fluorescent phosphoinositide sensors in rod photoreceptors demonstrated distinct subcellular distribution patterns of major phosphoinositides. The PI(4,5)P2 reporter was enriched in the inner segments and synapses, but was barely detected in the light-sensitive outer segments. The PI(4)P reporter was mostly found in the outer and inner segments and the areas around nuclei, but to a lesser degree in the synaptic region. These findings provide support for future mechanistic studies defining the biological significance of major mono- (PI(4)P) and bisphosphate (PI(4,5)P2) phosphatidylinositols in photoreceptor biology and retinal health.

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Insights into photoreceptor ciliogenesis revealed by animal models

Cited by 42 publications

References 397 publications

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

The myosin-tail homology domain of centrosomal protein 290 is essential for protein confinement between the inner and outer segments in photoreceptors

Phosphoinositide Profile of the Mouse Retina

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