Transcription factor Heat Shock Factor 1 (Hsf1), which the developing brain releases to shield the vital organ from the ravages of environmental stress, actually can contribute to impairing the embryonic brain when too much Hsf1 is produced, research scientists indicate. While the finding was made in a preclinical model, it raises questions about neural risks for human infants if their mothers drink alcohol in the first or second trimester of pregnancy.
When fetuses are chronically exposed to harmful agents in utero, such as alcohol, ethanol or methyl mercury, the experience can negatively affect fetal brain development in unpredictable ways. Some fetal brains show little or no damage, while some fetal brains suffer severe damage. By looking back to the earliest moments of embryonic brain development, an international research team sought to explain the molecular and cellular bases for complex congenital brain disorders that can result from exposure to such harmful agents.
"From a public health perspective, there is ongoing debate about whether there is any level of drinking by pregnant women that is 'safe,' " says principal investigator and senior author of the paper published in Nature Communications. "We gave ethanol to pregnant preclinical models and found their offspring's neural cells experienced widely differing responses to this environmental stress. It remains unclear which precise threshold of stress exposure represents the tipping point, transforming what should be a neuroprotective response into a damaging response. Even at lower levels of alcohol exposure, however, the risk for fetal neural cells is not zero," author adds.
The cerebral cortex - the thin outer layer of the cerebrum and cerebellum that enables the brain to process information - is particularly vulnerable to disturbances in the womb, the study authors write. To fend off insult, neural cells employ a number of self-preservation strategies, including launching the protective Hsf1-Heat shock protein (Hsp) signaling pathway that is used by a wide range of organisms, from single-cell microbes to humans. Developing fetuses activate Hsf1-Hsp signaling upon exposure to environmental stressors, some to no avail.
To help unravel the neurological mystery, the research sleuths used a method that allows a single molecule to fluoresce during stress exposure. They tapped specific environmental stressors, such as ethanol, hydrogen peroxide and methyl mercury - each of which are known to produce oxidative stress at defined concentrations. And, using an experimental model, they examined the Hsf1 activation pattern in the developing cerebral cortex by creating a marker, an encoding gene tagged with a type of fluorescent protein that makes it glow bright red.
"Our results suggest that heterogeneous events of abnormal brain development may occur probabilistically - which explains patterns of cortical malformations that vary with each individual, even when these individuals are exposed to similar levels of environmental stressors," author adds.
Among the more striking findings, neural cells with excessively high levels of Hsf1-Hsp activation due to ethanol exposure experience disruptions to normal development, with delayed migration by immature cortical neurons. For the fetal brain to develop normally, neurons need to migrate to precise places in the brain at just the right time to enable robust neural connections. When neurons fail to arrive at their destinations or get there too late, there can be gaps in the neural network, compromising efficient and effective communication across the brain's various regions.
"Even a short period of Hsf1 overactivation during prenatal development causes critical neuronal migration deficiency. The severity of deficiency depends on the duration of Hsf1 overactivation," author says. "Expression patterns vary, however, across various tissues. Stochastic response within individual cells may be largely responsible for variability seen within tissue and organs."
The research team found one bright spot: Cortical neurons that stalled due to lack of the microtubule-associated molecule Dcx were able to regain their ability to migrate properly when the gene was replenished after birth. A reduction in Hsf1 activity after birth, however, did not show the same ability to trigger the "reset" button on neural development.
"The finding suggests that genes other than microtubule-associated genes may play pivotal roles in ensuring that migrating neurons reach their assigned destinations in the brain at the right time - despite the added challenge of excessive Hsf1 activation," according to the senior author.
https://childrensnational.org/news-and-events/childrens-newsroom/2017/excess-production-of-transcription-factor-heat-shock-factor-1-can-delay-embryonic-neural-migration
https://www.nature.com/articles/ncomms15157
Excess transcription factor Heat Shock Factor 1 can delay embryonic neural migration
- 1,733 views
- Added
Edited
Latest News
Wiring of the human neocortex
By newseditor
Posted 24 Apr
Abusive drugs hijack natura…
By newseditor
Posted 23 Apr
Mechanism of action of the…
By newseditor
Posted 23 Apr
Role of fat in rare neurolo…
By newseditor
Posted 23 Apr
How protein synthesis in de…
By newseditor
Posted 22 Apr
Other Top Stories
Cell memory loss enables the production of stem cells
Read more
Sepsis: Stem cell therapy to repair muscle long-term impairment
Read more
Accumulation of differentiating intestinal stem cell progenies driv…
Read more
Retinal transplantation in primate models of retinitis pigmentosa
Read more
Regulation of germ layer mesoderm specification
Read more
Protocols
A programmable targeted pro…
By newseditor
Posted 23 Apr
MemPrep, a new technology f…
By newseditor
Posted 08 Apr
A tangible method to assess…
By newseditor
Posted 08 Apr
Stem cell-derived vessels-o…
By newseditor
Posted 06 Apr
Single-cell biclustering fo…
By newseditor
Posted 01 Apr
Publications
Integrative spatial analysi…
By newseditor
Posted 24 Apr
Time-series reconstruction…
By newseditor
Posted 24 Apr
Harnessing gastrointestinal…
By newseditor
Posted 24 Apr
Sex-specific modulation of…
By newseditor
Posted 24 Apr
Exploiting pancreatic cance…
By newseditor
Posted 23 Apr
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar