The chromatin-remodeling protein ATRX is critical for neuronal survival during corticogenesis

Abstract

Mutations in genes encoding chromatin-remodeling proteins, such as the ATRX gene, underlie a number of genetic disorders including several X-linked mental retardation syndromes; however, the role of these proteins in normal CNS development is unknown. Here, we used a conditional gene-targeting approach to inactivate Atrx, specifically in the forebrain of mice. Loss of ATRX protein caused widespread hypocellularity in the neocortex and hippocampus and a pronounced reduction in forebrain size. Neuronal "birthdating" confirmed that fewer neurons reached the superficial cortical layers, despite normal progenitor cell proliferation. The loss of cortical mass resulted from a 12-fold increase in neuronal apoptosis during early stages of corticogenesis in the mutant animals. Moreover, cortical progenitors isolated from Atrx-null mice undergo enhanced apoptosis upon differentiation. Taken together, our results indicate that ATRX is a critical mediator of cell survival during early neuronal differentiation. Thus, increased neuronal loss may contribute to the severe mental retardation observed in human patients.

Mutant ATRX: uncovering a new therapeutic target for glioma

“…This is followed by the activation of DNA- damage responses (DDR) and mitotic failure, which in turn triggers cell death in several cell types [30–32, 58]. In this instance, ATRX is implicated in DNA replication by assisting resolution of non-B DNA structures (such as G4), thus protecting stalled replication forks from collapsing [58].…”

“…Attempts to target Atrx in mouse embryonic stem (ES) cells reveal that knock out was lethal for these cells and conditionally Atrx-null mouse embryos (Heterozygous males) do not survive more than 10 days [29]. Moreover, the conditional inactivation of Atrx in the developing brain results in defects in neuronal differentiation, causing a decrease in the number of cells in the neocortex and hippocampus as well as a concomitant reduction in forebrain size [30]. Comparable effects in the development of other cell lineages were also characterized, such as in muscular cells [31], where the high levels of cell proliferation highlight the effects of Atrx -inactivation on DNA damage and replicative stress.…”

Atrx deletion in neurons leads to sexually-dimorphic dysregulation of miR-137 and spatial learning and memory deficits

“…Mice were exposed to a 12-hour-light/12-hour-dark cycle and with water and chow ad libitum. The Atrx loxP mice have been described previously 18 .…”

“…Male and female littermate floxed mice lacking the Cre allele were used as controls (Ctrl; Ctrl Fem ). Genotyping of tail biopsies for the presence of the floxed and Cre alleles was performed as described previously 18 . All procedures involving animals were conducted in accordance with the regulations of the Animals for Research Act of the province of Ontario and approved by the University of Western Ontario Animal Care and Use Committee (2017-048).…”

Optogenetic Stimulation Enhanced Neuronal Plasticities in Motor Recovery after Ischemic Stroke

“…As to axonal sprouting, several sprouting transcriptomes and molecules like EphA4, ATRX, Lingo1, and IGF have been evaluated to be responsible for axonal sprouting after stroke [32, 34, 67]. Among them, EphA4 and Lingo1 are growth inhibitors, while IGF is a growth-associated factor.…”