ZFIN ID: ZDB-PUB-160226-15
ATR promotes cilia signalling; links to developmental impacts
Stiff, T., Casar Tena, T., O'Driscoll, M., Jeggo, P.A., Philipp, M.
Date: 2016
Source: Human molecular genetics   25(8): 1574-87 (Journal)
Registered Authors:
Keywords: none
MeSH Terms:
  • Animals
  • Ataxia Telangiectasia Mutated Proteins/genetics
  • Ataxia Telangiectasia Mutated Proteins/metabolism*
  • Cell Line
  • Cilia/metabolism
  • Cilia/pathology*
  • DNA Replication
  • Disease Models, Animal
  • Dwarfism/genetics
  • Dwarfism/pathology*
  • Facies
  • Gene Expression Regulation, Developmental
  • Humans
  • Microcephaly/genetics
  • Microcephaly/pathology*
  • Signal Transduction
  • Zebrafish/embryology*
  • Zebrafish/genetics
  • Zebrafish/metabolism
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 26908596 Full text @ Hum. Mol. Genet.
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.