Variations in brain defects result from cellular mosaicism in the activation of heat shock signalling

Abstract

Repetitive prenatal exposure to identical or similar doses of harmful agents results in highly variable and unpredictable negative effects on fetal brain development ranging in severity from high to little or none. However, the molecular and cellular basis of this variability is not well understood. This study reports that exposure of mouse and human embryonic brain tissues to equal doses of harmful chemicals, such as ethanol, activates the primary stress response transcription factor heat shock factor 1 (Hsf1) in a highly variable and stochastic manner. While Hsf1 is essential for protecting the embryonic brain from environmental stress, excessive activation impairs critical developmental events such as neuronal migration. Our results suggest that mosaic activation of Hsf1 within the embryonic brain in response to prenatal environmental stress exposure may contribute to the resulting generation of phenotypic variations observed in complex congenital brain disorders.

Kcnn2 blockade reverses learning deficits in a mouse model of fetal alcohol spectrum disorders

“…To assess the impact of prenatal alcohol exposure (PAE) on motor skill learning in mice, we used the paradigm of ethanol (EtOH) exposure during corticogenesis 7 – 10 . Mice were exposed to EtOH in utero at embryonic days (E) 16 and 17, during which upper cortical layer neurons are predominantly generated 15 – 19 .…”

“…Our previous studies have revealed heterogeneous molecular responses through the activation of HS signaling, a canonical stress response pathway 11 , 14 , in neural progenitor cells in embryonic cortex immediately after environmental stress exposure 7 , 8 , 10 . However, it remains largely unknown how such heterogeneous responses in progenitor cells affect their progeny and contribute to behavioral abnormalities, such as motor skill learning impairment ( Fig.…”

“…Recently, we identified cell-to-cell variability among neural progenitor cells within the cerebral cortex in their acute molecular response to prenatal alcohol exposure, and that this activity is mediated by heterogeneous activation of heat shock (HS) signaling 7 – 10 . This acute activation of HS signaling occurs immediately in response to cellular stress 11 to protect progenitor cells 7 , 12 , 13 ; however, excessive activation can cause abnormal cell cycling and delay in radial migration of young neurons 10 , 13 . Together, with the evidence that HS signaling can mark epigenetic transcriptional memory 14 , these findings suggest that variable impacts associated with prenatal HS responses on later neural functions can be important therapeutic targets for cognitive and intellectual disabilities in FASD.…”

ABHD4-dependent developmental anoikis safeguards the embryonic brain

“…Prenatal ethanol exposure can cause several brain malformations including cortical dysplasia/ heterotopias and microcephaly, all indicating impaired migration and neurogenesis 16 . Importantly, ethanol is known to induce disruption of the adherens junction signaling machinery, to reduce the RGPC pool and to increase cell death, including anoikis 15,16,37,38 . Therefore, we hypothesized that ABHD4 may play a role in cell death associated with prenatal alcohol exposure.…”

Detection of local and remote cellular damage caused by spinal cord and peripheral nerve injury using a heat shock signaling reporter system

“…From the obtained 3 founder lines (#B9, B11 and B49), the strongest (most sensitive) reporter line, #B9, was selected for the study ( Torii et al, 2017 ). The genetic insertion site has been defined, indicating that reporter expression is independent of the influence of transgene locus ( Ishii et al, 2017 ). For routine genotyping, oligonucleotide PCR primers; Forward 5’-AAGGTGTACGTGAAGCACCC-3’, Reverse 5’-CCCATGGTCTTCTTCTGCAT-3’ were used for the amplification of the 250 bp partial sequence of the DsRed2 gene with Hotstar taq DNA polymerase kit (Qiagen).…”