The Ciliopathy Gene <i>ahi1</i> Is Required for Zebrafish Cone Photoreceptor Outer Segment Morphogenesis and Survival

Lessieur, Emma M; Fogerty, Joseph; Gaivin, Robert J.; Song, Ping; Perkins, Brian D.

doi:10.1167/iovs.16-20326

Cited by 35 publications

(50 citation statements)

References 44 publications

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“…These phenotypes were not 335 fully penetrant with only 29% of mutant larvae exhibiting such characteristics (17 of 58 336 confirmed cep290 fh297/fh297 mutants). Furthermore, these phenotypes were similar to, but distinct 337 from phenotypes of other zebrafish mutants with defective cilia formation, such as ift88 or 338 cc2d2a mutants, which exhibit a ventral axis curvature [40,46,47]. All cep290 fh297/fh297 mutants 339 exhibited normal otolith numbers and only 6.8% (4 of 58 confirmed cep290 fh297/fh297 mutants) 340 developed kidney cysts by 5 dpf.…”

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confidence: 71%

“…Contrast sensitivity was assessed as described previously [38,39]. For the spatial 227 frequency response function [39,40], the contrast was held constant at 70% and we tested predicted to truncate the protein by almost half (Fig. 1A) and is near a similar mutation in 307 humans (p.Gln1265X) that associated with LCA and JBTS (https://cep290base.cmgg.be/).…”

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confidence: 99%

“…Because larval zebrafish rely exclusively on cone function at 381 5-6 dpf [53,54], all recordings were done under photopic conditions [55]. We measured the 382 OKR gain, which is defined by the ratio between stimulus velocity and eye velocity [38][39][40], of 383 wild-type, and cep290 fh297/fh297 mutants between 5-6 dpf using established parameters [39,56] 384 and reproduced by our laboratory [38,40]. Wild-type larvae (n = 12) showed a linear 385 relationship between gain and the logarithm of contrast (Fig.…”

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confidence: 99%

“…The Arl13b protein is required for axoneme extension and photoreceptor 593 outer segment formation [34]. Importantly, the zebrafish cc2d2a -/and ahi1 -/mutants show 594 defects in photoreceptor OS structure during larval stages [40,47] while the arl13b -/zebrafish 595 mutant undergoes a progressive photoreceptor degeneration [35]. The known and proposed 596 biochemical and genetic interactions, as well as similar protein localization patterns in the 597 transition zone and axoneme, suggested that these genes could potentially modulate 598 phenotypes associated with Cep290 mutations.…”

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Ciliary Genesarl13b,ahi1andcc2d2aDifferentially Modify Expression of Visual Acuity Phenotypes but do not Enhance Retinal Degeneration due to Mutation ofcep290 in Zebrafish

Lessieur

Song

Nivar

et al. 2019

Preprint

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Mutations in the gene Centrosomal Protein 290 kDa (CEP290) result in multiple ciliopathies ranging from the neonatal lethal disorder Meckel-Gruber Syndrome to multi-systemic disorders such as Joubert Syndrome and Bardet-Biedl Syndrome to nonsyndromic diseases like Leber Congenital Amaurosis (LCA) and retinitis pigmentosa. Results from model organisms and human genetics studies, have suggest that mutations in genes encoding protein components of the transition zone (TZ) and other cilia-associated proteins can function as genetic modifiers and be a source for CEP290 pleiotropy. We investigated the zebrafish cep290fh297/fh297 mutant, which encodes a nonsense mutation (p.Q1217*). This mutant is viable as adults, exhibits scoliosis, and undergoes a slow, progressive cone degeneration. The cep290fh297/fh297 mutants showed partial mislocalization of the transmembrane protein rhodopsin but not of the prenylated proteins rhodopsin kinase (GRK1) or the rod transducin subunit GNB1. Surprisingly, photoreceptor degeneration did not trigger proliferation of Müller glia, but proliferation of rod progenitors in the outer nuclear layer was significantly increased. To determine if heterozygous mutations in other cilia genes could exacerbate retinal degeneration, we bred cep290fh297/fh297 mutants to arl13b, ahi1, and cc2d2a mutant zebrafish lines. While cep290fh297/fh297 mutants lacking a single allele of these genes did not exhibit accelerated photoreceptor degeneration, loss of one alleles of arl13b or ahi1 reduced visual performance in optokinetic response assays at 5 days post fertilization. Our results indicate that the cep290fh297/fh297 mutant is a useful model to study the role of genetic modifiers on photoreceptor degeneration in zebrafish and to explore how progressive photoreceptor degeneration influences regeneration in adult zebrafish.Nonstandard abbreviationsBBSBardet-Biedl SyndromeCOScone outer segmentsDpfDays post fertilizationGNB1rod transducin β subunitGRK1rhodopsin kinaseJTBSJoubert SyndromeLCALeber Congenital AmaurosisMKSMeckel SyndromeNPHPnephronophthisisOKRoptokinetic responsePNApeanut agglutinin lectinROSrod outer segmentsRP2Retinitis Pigmentosa 2

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confidence: 71%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Ciliary Genesarl13b,ahi1andcc2d2aDifferentially Modify Expression of Visual Acuity Phenotypes but do not Enhance Retinal Degeneration due to Mutation ofcep290 in Zebrafish

Lessieur

Song

Nivar

et al. 2019

Preprint

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“…Optokinetic response (OKR) measurements were performed as previously described (Daniele et al, 2016;Lessieur et al, 2017). Larvae at 5 dpf were assessed for contrast sensitivity using a VisioTracker system (VisioTracker 302060 Series, TSE Systems, GmbH Bad Homburg, Gemany).…”

Section: Behavioral Assays Video Recording and Analysismentioning

confidence: 99%

Pregnancy associated plasma protein-aa (Pappaa) regulates photoreceptor synaptic development to mediate visually guided behavior

Miller

Howe

Krause

et al. 2018

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To guide behavior, sensory systems detect the onset and offset of stimuli and process these distinct inputs via parallel pathways. In the retina, this strategy is implemented by splitting neural signals for light onset and offset via synapses connecting photoreceptors to ON and OFF bipolar cells, respectively. It remains poorly understood which molecular cues establish the architecture of this synaptic configuration to split light onset and offset signals. A mutant with reduced synapses between photoreceptors and one bipolar cell type, but not the other, could reveal a critical cue. From this approach, we report a novel synaptic role pregnancy associated plasma protein aa (pappaa) in promoting the structure and function of cone synapses that transmit light offset information. (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/257840 doi: bioRxiv preprint first posted online Jan. 31, 2018; Significance StatementDistinct sensory inputs, like stimulus onset and offset, are often split at distinct synapses into parallel circuits for processing. In the retina, photoreceptors and ON and OFF bipolar cells form discrete synapses to split neural signals coding light onset and offset, respectively. The molecular cues that establish this synaptic configuration to specifically convey light onset or offset remain unclear.Our work reveals a novel cue: pregnancy associated plasma protein aa (pappaa), which regulates photoreceptor synaptic structure and function to specifically transmit light offset information. Pappaa is a metalloprotease that stimulates local insulin-like growth factor 1 (IGF1) signaling. IGF1 promotes various aspects of synaptic development and function and is broadly expressed; thus requiring local regulators, like Pappaa, to govern its specificity.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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Mutations in ARMC9, which Encodes a Basal Body Protein, Cause Joubert Syndrome in Humans and Ciliopathy Phenotypes in Zebrafish

Weghe

Rusterholz

Latour

et al. 2017

The American Journal of Human Genetics

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Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by hypotonia, ataxia, abnormal eye movements, and variable cognitive impairment. It is defined by a distinctive brain malformation known as the "molar tooth sign" on axial MRI. Subsets of affected individuals have malformations such as coloboma, polydactyly, and encephalocele, as well as progressive retinal dystrophy, fibrocystic kidney disease, and liver fibrosis. More than 35 genes have been associated with JS, but in a subset of families the genetic cause remains unknown. All of the gene products localize in and around the primary cilium, making JS a canonical ciliopathy. Ciliopathies are unified by their overlapping clinical features and underlying mechanisms involving ciliary dysfunction. In this work, we identify biallelic rare, predicted-deleterious ARMC9 variants (stop-gain, missense, splice-site, and single-exon deletion) in 11 individuals with JS from 8 families, accounting for approximately 1% of the disorder. The associated phenotypes range from isolated neurological involvement to JS with retinal dystrophy, additional brain abnormalities (e.g., heterotopia, Dandy-Walker malformation), pituitary insufficiency, and/or synpolydactyly. We show that ARMC9 localizes to the basal body of the cilium and is upregulated during ciliogenesis. Typical ciliopathy phenotypes (curved body shape, retinal dystrophy, coloboma, and decreased cilia) in a CRISPR/Cas9-engineered zebrafish mutant model provide additional support for ARMC9 as a ciliopathy-associated gene. Identifying ARMC9 mutations as a cause of JS takes us one step closer to a full genetic understanding of this important disorder and enables future functional work to define the central biological mechanisms underlying JS and other ciliopathies.

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The Ciliopathy Gene ahi1 Is Required for Zebrafish Cone Photoreceptor Outer Segment Morphogenesis and Survival

Cited by 35 publications

References 44 publications

Ciliary Genesarl13b,ahi1andcc2d2aDifferentially Modify Expression of Visual Acuity Phenotypes but do not Enhance Retinal Degeneration due to Mutation ofcep290 in Zebrafish

Ciliary Genesarl13b,ahi1andcc2d2aDifferentially Modify Expression of Visual Acuity Phenotypes but do not Enhance Retinal Degeneration due to Mutation ofcep290 in Zebrafish

Pregnancy associated plasma protein-aa (Pappaa) regulates photoreceptor synaptic development to mediate visually guided behavior

Mutations in ARMC9, which Encodes a Basal Body Protein, Cause Joubert Syndrome in Humans and Ciliopathy Phenotypes in Zebrafish

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