Early defects in photoreceptor outer segment morphogenesis in zebrafish ift57, ift88 and ift172 Intraflagellar Transport mutants

Sukumaran, Sujita; Perkins, Brian D.

doi:10.1016/j.visres.2008.12.009

Cited by 84 publications

(98 citation statements)

References 38 publications

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“…Histological sections of the eye showed that in ift172 hi2211 mutants, whereas the outer segment, a form of specialized cilia of the photoreceptor layer, was greatly diminished, the other layers were relatively well maintained (Fig. 4A), consistent with previous reports of other IFT mutants (41,42). Moreover, the structure of the eye in seahorse hi3308 mutants seems normal (Fig.…”

Section: Resultssupporting

confidence: 89%

Reptin/Ruvbl2 is a Lrrc6/Seahorse interactor essential for cilia motility

Lei

Yuan

Cao

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Primary ciliary dyskinesia (PCD) is an autosomal recessive disease caused by defective cilia motility. The identified PCD genes account for about half of PCD incidences and the underlying mechanisms remain poorly understood. We demonstrate that Reptin/ Ruvbl2, a protein known to be involved in epigenetic and transcriptional regulation, is essential for cilia motility in zebrafish. We further show that Reptin directly interacts with the PCD protein Lrrc6/Seahorse and this interaction is critical for the in vivo function of Lrrc6/Seahorse in zebrafish. Moreover, whereas the expression levels of multiple dynein arm components remain unchanged or become elevated, the density of axonemal dynein arms is reduced in reptin hi2394 mutants. Furthermore, Reptin is highly enriched in the cytosol and colocalizes with Lrrc6/Seahorse. Combined, these results suggest that the Reptin-Lrrc6/Seahorse complex is involved in dynein arm formation. We also show that although the DNA damage response is induced in reptin hi2394 mutants, it remains unchanged in cilia biogenesis mutants and lrrc6/seahorse mutants, suggesting that increased DNA damage response is not intrinsic to ciliary defects and that in vertebrate development, Reptin functions in multiple processes, both cilia specific and cilia independent.ciliopathy | chromatin remodeling complex | dynein arm assembly factor A lthough the sensory function of the cilium has garnered significant attention only in the past decade, defective cilia motility was recognized nearly four decades ago as the cause of primary (genetic) ciliary dyskinesia (PCD) (1). PCD is a group of rare human genetic diseases characterized by recurrent infections of the respiratory system, male infertility, and frequently laterality defects, all of which are tightly linked to cilia motility abnormalities. Up to now, 19 PCD genes have been identified (2-20). However, combined they account for about 50% of all PCD cases, suggesting the existence of multiple additional causative genes. Despite such significant advances, our understanding of how cilia motility is regulated is limited and the list of genes involved in cilia motility remains incomplete.In motile cilia or flagella, dynein arms are large protein complexes powering cilia motility. Not surprisingly, multiple PCD genes encode dynein arm components, including DNAL1, DNAI1, DNAI2, DNAH5, and DNAH11 (2-6). In addition, it is understood that dynein arm subunits are preassembled in the cytosol, transported into cilia/flagellum, and docked onto the axoneme, although the underlying mechanisms are poorly understood (21). In recent years, three PCD genes, i.e., DNAAF1/LRRC50 (7, 8), DNAAF2/ KTU (9), and DNAAF3/PF22 (10) have been shown to be involved in the assembly of dynein arm subunits, highlighting the relevance and importance of this process in cilia motility and PCD.Very recently, mutations in human LRRC6/SEAHORSE were linked to PCD (18). Similar to the three known dynein arm assembly factors, mutations in LRRC6/SEAHORSE lead to the absence of both the outer...

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Section: Resultssupporting

confidence: 89%

Reptin/Ruvbl2 is a Lrrc6/Seahorse interactor essential for cilia motility

Lei

Yuan

Cao

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…The IFT-B particle IFT88 (Tg737 or Polaris), located at basal bodies and axonemes, is required for anterograde trafficking and ciliary assembly (10,14). Chlamydomonas mutants lacking IFT88 are viable but do not form flagella (14), and zebrafish Ift88 mutants never develop photoreceptor outer segments (15). Germline deletions of IFT88 are embryonically lethal (14,16), and hypomorphic mutations (Tg737 orpk mice) cause complex ciliopathies affecting multiple tissues including photoreceptors, kidney, and olfactory neurons (17)(18)(19)(20).…”

Section: Intraflagellar Transport (Ift) Is a Bidirectional Ciliary Trmentioning

confidence: 99%

Heterotrimeric Kinesin-2 (KIF3) Mediates Transition Zone and Axoneme Formation of Mouse Photoreceptors

Jiang

Wei

Ronquillo

et al. 2015

Journal of Biological Chemistry

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Background: Heterotrimeric kinesin-2 (KIF3) has been implicated in intraflagellar trafficking of photoreceptor membrane proteins by IFT. Results: KIF3 and IFT88 are required for transition zone and axoneme formation, but are dispensable for rhodopsin trafficking. Conclusion: Transmembrane proteins, including rhodopsin, traffic to the OS even when IFT is disabled. Significance: KIF3 builds and maintains the photoreceptor transition zone and axoneme that are essential for photoreceptor integrity and vision.

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“…Moreover, the VKORC1 protein is an essential component of the blood coagulation system [73-75]. Finally, IFT57 has been shown to modulate intraflagellar transport in photoreceptor cells [76,77]. Since we performed co-IP using mouse whole-brain post-nuclear supernatants, it is understandable that we did not detect the nuclear transport protein Importin α-P1 [78], the activated NFATc1, NFATc2, and NFATc4 transcription factor proteins (reviewed in [79]), or CSPP1, which is involved in mitotic progression, cytokinesis, and ciliogenesis [80-82].…”

Section: Resultsmentioning

confidence: 99%

A mass spectrometry-based proteomic analysis of Homer2-interacting proteins in the mouse brain

Goulding

Szumlinski

Contet

et al. 2017

Journal of Proteomics

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In the brain, the Homer protein family modulates excitatory signal transduction and receptor plasticity through interactions with other proteins in dendritic spines. Homer proteins are implicated in a variety of psychiatric disorders such as schizophrenia and addiction. Since Homers serve as scaffolding proteins, identifying their interaction partners is an important first step in understanding their biological function and could help design novel therapeutic strategies. The present study set out to document Homer2-interacting proteins in the mouse brain using a co-immunoprecipitation-based mass spectrometry approach. Homer2 knockout samples were used to filter out non-specific interactors. We found that in the brain, Homer2 interacts with a limited subset of its previously reported interaction partners (3 out of 31). Importantly, we detected an additional 15 “novel” Homer2-interacting proteins, most of which are part of the N-methyl-D-aspartate receptor signaling pathway. These results corroborate the central role Homer2 plays in glutamatergic transmission and expand the network of proteins potentially contributing to the behavioral abnormalities associated with altered Homer2 expression.

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Early defects in photoreceptor outer segment morphogenesis in zebrafish ift57, ift88 and ift172 Intraflagellar Transport mutants

Cited by 84 publications

References 38 publications

Reptin/Ruvbl2 is a Lrrc6/Seahorse interactor essential for cilia motility

Reptin/Ruvbl2 is a Lrrc6/Seahorse interactor essential for cilia motility

Heterotrimeric Kinesin-2 (KIF3) Mediates Transition Zone and Axoneme Formation of Mouse Photoreceptors

A mass spectrometry-based proteomic analysis of Homer2-interacting proteins in the mouse brain

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