ATR-hippo mediates force signalling to nuclear f-actin and links mechanotransduction to neurological disorders.

ABSTRACT: The mechanical environment is sensed through cell-matrix contacts with the cytoskeleton, but how signals transit the nuclear envelope to impact cell fate decisions remains unknown. Nuclear actin coordinates chromatin motility during differentiation, plasticity and genome maintenance, yet it also remains unclear how nuclear actin responds to mechanical force. Intriguingly, ATR translocates to the nuclear envelope to protect the nucleus during cell motility or compression. Here, we show that ATR drives nuclear actin assembly via recruitment of Filamin-A to the inner nuclear membrane through binding of the hippo pathway scaffold and ATR-substrate, RASSF1A. Moreover, we demonstrate how germline RASSF1 mutation disables nuclear mechanotransduction resulting in cerebral cortex thinning and associates with common psychological traits. Thus, defective mechanical-regulated pathways may provide an explanation for complex neurological disorders.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: iolanda Vendrell  

LAB HEAD: Eric O'neill

PROVIDER: PXD057905 | Pride | 2025-05-07

REPOSITORIES: Pride