PUBLICATION
ATR promotes cilia signalling; links to developmental impacts
- Authors
- Stiff, T., Casar Tena, T., O'Driscoll, M., Jeggo, P.A., Philipp, M.
- ID
- ZDB-PUB-160226-15
- Date
- 2016
- Source
- Human molecular genetics 25(8): 1574-87 (Journal)
- Registered Authors
- Philipp, Melanie
- Keywords
- none
- MeSH Terms
-
- DNA Replication
- Gene Expression Regulation, Developmental
- Cilia/metabolism
- Cilia/pathology*
- Disease Models, Animal
- Humans
- Cell Line
- Animals
- Microcephaly/genetics
- Microcephaly/pathology*
- Dwarfism/genetics
- Dwarfism/pathology*
- Signal Transduction
- Zebrafish/embryology*
- Zebrafish/genetics
- Zebrafish/metabolism
- Facies
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- Ataxia Telangiectasia Mutated Proteins/genetics
- Ataxia Telangiectasia Mutated Proteins/metabolism*
- PubMed
- 26908596 Full text @ Hum. Mol. Genet.
Citation
Stiff, T., Casar Tena, T., O'Driscoll, M., Jeggo, P.A., Philipp, M. (2016) ATR promotes cilia signalling; links to developmental impacts. Human molecular genetics. 25(8):1574-87.
Abstract
Mutations in ATR (Ataxia telangiectasia and RAD3-related) cause Seckel Syndrome (ATR-SS), a microcephalic primordial dwarfism (MPD) disorder. Hitherto, the clinical manifestation of ATR deficiency has been attributed to its canonical role in DNA damage response signalling following replication fork stalling/collapse. Here, we show that ATR regulates cilia-dependent signalling in a manner that can be uncoupled from its function during replication. ATR-depleted or patient-derived ATR-SS cells form cilia of slightly reduced length but are dramatically impaired in cilia-dependent signalling functions, including growth factor and Sonic hedgehog signalling. To better understand the developmental impact of ATR loss of function, we also used zebrafish as a model. Zebrafish embryos depleted of Atr resembled ATR-SS morphology, showed a modest but statistically significant reduction in cilia length and other morphological features indicative of cilia dysfunction. Additionally, they displayed defects in left-right asymmetry including ambiguous expression of southpaw, incorrectly looped hearts and randomised localisation of internal organs including the pancreas, features typically conferred by cilia dysfunction. Our findings reveal a novel role for ATR in cilia signalling distinct from its canonical function during replication and strengthen emerging links between cilia function and development.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping