Neurodegeneration in the olfactory bulb and olfactory deficits in the Ccdc66 -/- mouse model for retinal degeneration

Schreiber, S.; Petrasch‐Parwez, Elisabeth; Porrmann-Kelterbaum, Elke; Förster, Eckart; Epplen, Jörg T.; Gerding, Wanda M.

doi:10.1016/j.ibror.2018.08.004

Cited by 9 publications

(9 citation statements)

References 37 publications

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“…Curiously, CCDC66 may impact smell as well as vision. CCDC66 −/− mice also display neurodegeneration of the olfactory bulb, and have reduced odor discrimination performance of lemon smells ( 72 ). The ecological significance of this result, if any, is unclear at present but may warrant future attention.…”

Section: Discussionmentioning

confidence: 99%

The genomics of ecological flexibility, large brains, and long lives in capuchin monkeys revealed with fecalFACS

Orkin

Montague

Tejada‐Martinez

et al. 2021

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

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Ecological flexibility, extended lifespans, and large brains have long intrigued evolutionary biologists, and comparative genomics offers an efficient and effective tool for generating new insights into the evolution of such traits. Studies of capuchin monkeys are particularly well situated to shed light on the selective pressures and genetic underpinnings of local adaptation to diverse habitats, longevity, and brain development. Distributed widely across Central and South America, they are inventive and extractive foragers, known for their sensorimotor intelligence. Capuchins have among the largest relative brain size of any monkey and a lifespan that exceeds 50 y, despite their small (3 to 5 kg) body size. We assemble and annotate a de novo reference genome for Cebus imitator. Through high-depth sequencing of DNA derived from blood, various tissues, and feces via fluorescence-activated cell sorting (fecalFACS) to isolate monkey epithelial cells, we compared genomes of capuchin populations from tropical dry forests and lowland rainforests and identified population divergence in genes involved in water balance, kidney function, and metabolism. Through a comparative genomics approach spanning a wide diversity of mammals, we identified genes under positive selection associated with longevity and brain development. Additionally, we provide a technological advancement in the use of noninvasive genomics for studies of free-ranging mammals. Our intra- and interspecific comparative study of capuchin genomics provides insights into processes underlying local adaptation to diverse and physiologically challenging environments, as well as the molecular basis of brain evolution and longevity.

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Section: Discussionmentioning

confidence: 99%

The genomics of ecological flexibility, large brains, and long lives in capuchin monkeys revealed with fecalFACS

Orkin

Montague

Tejada‐Martinez

et al. 2021

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

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“…ERG in these mice pointed to primary rod degeneration accompanied, to a lesser extent, by cone degeneration, following a time course comparable to RP in humans rather than other more rapidly progressive RP mouse models. In a more recent study, a substantial olfactory nerve fiber degeneration and alteration of olfaction-related behavior was described in aged Ccdc66−/− mice 47 . As both photoreceptors and olfactory sensory neurons that undergo degeneration are ciliated, Ccdc66 −/− mice appear to represent a ciliopathy-like disease.…”

Section: Discussionmentioning

confidence: 92%

CCDC66 frameshift variant associated with a new form of early-onset progressive retinal atrophy in Portuguese Water Dogs

Murgiano

Becker

Spector

et al. 2020

Sci Rep

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Aberrant photoreceptor function or morphogenesis leads to blinding retinal degenerative diseases, the majority of which have a genetic aetiology. A variant in PRCD previously identified in Portuguese Water Dogs (PWDs) underlies prcd (progressive rod-cone degeneration), an autosomal recessive progressive retinal atrophy (PRA) with a late onset at 3–6 years of age or older. Herein, we have identified a new form of early-onset PRA (EOPRA) in the same breed. Pedigree analysis suggested an autosomal recessive inheritance. Four PWD full-siblings affected with EOPRA diagnosed at 2–3 years of age were genotyped (173,661 SNPs) along with 2 unaffected siblings, 2 unaffected parents, and 15 unrelated control PWDs. GWAS, linkage analysis and homozygosity mapping defined a 26-Mb candidate region in canine chromosome 20. Whole-genome sequencing in one affected dog and its obligatory carrier parents identified a 1 bp insertion (CFA20:g.33,717,704_33,717,705insT (CanFam3.1); c.2262_c.2263insA) in CCDC66 predicted to cause a frameshift and truncation (p.Val747SerfsTer8). Screening of an extended PWD population confirmed perfect co-segregation of this genetic variant with the disease. Western blot analysis of COS-1 cells transfected with recombinant mutant CCDC66 expression constructs showed the mutant transcript translated into a truncated protein. Furthermore, in vitro studies suggest that the mutant CCDC66 is mislocalized to the nucleus relative to wild type CCDC66. CCDC66 variants have been associated with inherited retinal degenerations (RDs) including canine and murine ciliopathies. As genetic variants affecting the primary cilium can cause ciliopathies in which RD may be either the sole clinical manifestation or part of a syndrome, our findings further support a role for CCDC66 in retinal function and viability, potentially through its ciliary function.

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“…CCDC66 has been implicated in several developmental disorders including retinal degeneration and Joubert syndrome (Dekomien et al, 2010; Gerding et al, 2011; Latour et al, 2020; Murgiano et al, 2020; Schreiber et al, 2018). Consistent with its link to ciliopathies, we and others previously showed that retinal degeneration mutations disrupt its ciliary functions and interactions (Conkar et al, 2017; Murgiano et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…We previously characterized coiled coil protein 66 (CCDC66) as a MAP and a regulator of primary cilium formation and composition in quiescent cells(Conkar et al, 2019; Conkar et al, 2017). It was originally described as a gene mutated in retinal degeneration and later characterized for its retinal and olfactory functions using CCDC66 -/- mouse (Dekomien et al, 2010; Gerding et al, 2011; Murgiano et al, 2020; Schreiber et al, 2018). Recently, CCDC66 was identified as part of the Joubert syndrome interaction network consisting of other MAPs such as CSPP1, TOGARAM1 and CEP290 (Latour et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

The ciliopathy protein CCDC66 controls mitotic progression and cytokinesis by promoting microtubule nucleation and organization

Batman

Deretic

Fırat-Karalar

2022

Preprint

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Precise spatiotemporal control of microtubule nucleation and organization is critical for faithful segregation of cytoplasmic and genetic material during cell division and signaling via the primary cilium in quiescent cells. Microtubule-associated proteins (MAPs) govern assembly, maintenance, and remodeling of diverse microtubule arrays. While a set of conserved MAPs are only active during cell division, an emerging group of MAPs acts as dual regulators in dividing and non-dividing cells. Here, we elucidated the nonciliary functions and molecular mechanism of action of the ciliopathy-linked protein CCDC66, which we previously characterized as a regulator of ciliogenesis in quiescent cells. We showed that CCDC66 dynamically localizes to the spindle poles, the bipolar spindle, the spindle midzone, the central spindle and the midbody in dividing cells and interacts with the core machinery of centrosome maturation and MAPs involved in cell division. Loss-of-function experiments revealed its functions during mitotic progression and cytokinesis. Specifically, CCDC66 depletion resulted in defective spindle assembly and positioning, kinetochore fiber stability, chromosome alignment in metaphase as well as central spindle and midbody assembly and organization in anaphase and cytokinesis. Notably, CCDC66 regulates mitotic microtubule nucleation via noncentrosomal and centrosomal pathways via recruitment of gamma-tubulin to the spindle poles and the spindle. Additionally, CCDC66 bundles microtubules in vitro and in cells by its C-terminal microtubule-binding domain. Phenotypic rescue experiments showed that the microtubule and centrosome-associated pools of CCDC66 individually or cooperatively mediate its mitotic and cytokinetic functions. Collectively, our findings identify CCDC66 as a multifaceted regulator of the nucleation and organization of the diverse mitotic and cytokinetic microtubule arrays and provides new insight into nonciliary defects that underlie ciliopathies.

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Neurodegeneration in the olfactory bulb and olfactory deficits in the Ccdc66 -/- mouse model for retinal degeneration

Cited by 9 publications

References 37 publications

The genomics of ecological flexibility, large brains, and long lives in capuchin monkeys revealed with fecalFACS

The genomics of ecological flexibility, large brains, and long lives in capuchin monkeys revealed with fecalFACS

CCDC66 frameshift variant associated with a new form of early-onset progressive retinal atrophy in Portuguese Water Dogs

The ciliopathy protein CCDC66 controls mitotic progression and cytokinesis by promoting microtubule nucleation and organization

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