Pot1a prevents telomere dysfunction and ATM-dependent neuronal loss.

The Journal of neuroscience : the official journal of the Society for Neuroscience (2014-06-06)
Youngsoo Lee, Eric J Brown, Sandy Chang, Peter J McKinnon
ABSTRACT

Genome stability is essential for neural development and the prevention of neurological disease. Here we determined how DNA damage signaling from dysfunctional telomeres affects neurogenesis. We found that telomere uncapping by Pot1a inactivation resulted in an Atm-dependent loss of cerebellar interneurons and granule neuron precursors in the mouse nervous system. The activation of Atm by Pot1a loss occurred in an Atr-dependent manner, revealing an Atr to Atm signaling axis in the nervous system after telomere dysfunction. In contrast to telomere lesions, Brca2 inactivation in neural progenitors also led to ablation of cerebellar interneurons, but this did not require Atm. These data reveal that neural cell loss after DNA damage selectively engages Atm signaling, highlighting how specific DNA lesions can dictate neuropathology arising in human neurodegenerative syndromes.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
DAPI, for nucleic acid staining
Sigma-Aldrich
Sodium deoxycholate, ≥97% (titration)
Sigma-Aldrich
MOPS, ≥99.5% (titration)
Sigma-Aldrich
DL-Dithiothreitol solution, BioUltra, for molecular biology, ~1 M in H2O
Supelco
DL-Dithiothreitol solution, 1 M in H2O
Sigma-Aldrich
Sodium deoxycholate, BioXtra, ≥98.0% (dry matter, NT)
Sigma-Aldrich
MOPS, BioPerformance Certified, suitable for cell culture, ≥99.5% (titration)
Sigma-Aldrich
4-(2-Aminoethyl)benzenesulfonyl fluoride hydrochloride, ≥97.0% (HPLC)
Supelco
Pefabloc® SC, analytical standard
SAFC
Sodium deoxycholate
Sigma-Aldrich
MOPS, BioUltra, for molecular biology, ≥99.5% (T)
Sigma-Aldrich
MOPS, BioXtra, ≥99.5% (titration)
SAFC
MOPS
Sigma-Aldrich
MOPS, anhydrous, free-flowing, Redi-Dri, ≥99.5%