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2016 ; 25
(8
): 1574-87
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ATR promotes cilia signalling: links to developmental impacts
#MMPMID26908596
Stiff T
; Casar Tena T
; O'Driscoll M
; Jeggo PA
; Philipp M
Hum Mol Genet
2016[Apr]; 25
(8
): 1574-87
PMID26908596
show ga
Mutations in ATR(ataxia telangiectasia and RAD3-related) cause Seckel syndrome
(ATR-SS), a microcephalic primordial dwarfism 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
randomized localization 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.
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