ATR promotes cilia signalling: links to developmental impacts

Area of Science:

• Cell Biology
• Developmental Biology
• Genetics

Background:

• Mutations in ATR (ataxia telangiectasia and RAD3-related) cause Seckel syndrome (ATR-SS), a microcephalic primordial dwarfism disorder.
• The established role of ATR is in DNA damage response signaling, particularly during replication stress.

Purpose of the Study:

• To investigate the role of ATR in cilia-dependent signaling pathways.
• To determine if ATR's function in cilia signaling is independent of its canonical DNA replication role.
• To elucidate the developmental impact of ATR loss-of-function in a model organism.

Main Methods:

• Utilized ATR-depleted and patient-derived ATR-SS cell lines.
• Examined cilia length and signaling in these cells.
• Employed zebrafish embryos to model ATR loss-of-function, assessing morphology and developmental defects.

Main Results:

• ATR-depleted cells exhibited reduced cilia length and impaired cilia-dependent signaling (growth factor, Sonic hedgehog).
• Zebrafish embryos with depleted Atr showed Seckel syndrome-like morphology and reduced cilia length.
• Zebrafish displayed defects in left-right asymmetry and organ development, indicative of cilia dysfunction.

Conclusions:

• ATR plays a novel role in regulating cilia-dependent signaling, distinct from its DNA replication checkpoint function.
• This newly identified ATR function in cilia signaling has significant implications for understanding developmental disorders like Seckel syndrome.
• The findings highlight the intricate connection between cilia function and embryonic development.