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Neurulation is the embryological process which forms the precursors of the central nervous system and occurs after gastrulation has established the three primary cell layers of the embryo: ectoderm, mesoderm, and endoderm. In humans, the majority of this system is formed via primary neurulation, in which the central portion of the ectoderm—originally appearing as a flat sheet of cells—folds upwards and inwards, sealing off to form a hollow neural tube. As development proceeds, the anterior...
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In Vivo Targeting of Neural Progenitor Cells in Ferret Neocortex by In Utero Electroporation
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ATR maintains select progenitors during nervous system development.

Youngsoo Lee1, Erin R P Shull, Pierre-Olivier Frappart

  • 1Department of Genetics, St Jude Children's Research Hospital, Memphis, TN 38105, USA.

The EMBO Journal
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ATM and rad3-related (ATR) kinase is crucial for DNA replication stress signaling. Its loss impacts neurogenesis late in neural development, affecting specific progenitor cells and demonstrating selective roles in the nervous system.

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Area of Science:

  • Molecular Biology
  • Neuroscience
  • Genetics

Background:

  • The ATR (ATM and rad3-related) checkpoint kinase is vital for signaling DNA replication stress.
  • ATR dysfunction is linked to the neurodevelopmental disorder ATR-Seckel syndrome.
  • Understanding ATR's role in neurogenesis is crucial for comprehending brain development and related disorders.

Purpose of the Study:

  • To investigate the function of ATR during neurogenesis in the murine nervous system.
  • To determine the impact of conditional Atr deletion on neural progenitor cells and brain development.
  • To elucidate the specific spatiotemporal roles of ATR in maintaining genomic integrity during neurogenesis.

Main Methods:

  • Conditional deletion of the Atr gene in the murine nervous system, both broadly and in restricted regions (dorsal telencephalon).
  • Analysis of neurogenesis, progenitor cell proliferation, and apoptosis in Atr-deficient brains.
  • Investigation of the involvement of p53 and p16(Ink4a/Arf) pathways, as well as coincident inactivation of Atm.

Main Results:

  • ATR loss impacted neurogenesis late in neural development, affecting specific progenitor populations.
  • Atr-deficient cerebellar progenitors exhibited p53-independent proliferation arrest, while other brain regions showed partially p53-dependent apoptosis.
  • Nervous system-specific p53 loss did not exacerbate Atr inactivation outcomes, and Atm inactivation did not alter the Atr-deletion phenotype.

Conclusions:

  • ATR functions in a selective spatiotemporal manner to monitor genomic integrity during neurogenesis, rather than having a general role in preventing replication stress.
  • The nervous system exhibits distinct responses to ATR inactivation compared to other organs, with limited exacerbation by p53 loss.
  • Related DNA damage-response kinases ATR and ATM play non-overlapping roles in the brain.