Long-term spatial tracking of cells affected by environmental insults

Abstract

Background Harsh environments surrounding fetuses and children can induce cellular damage in the developing brain, increasing the risk of intellectual disability and other neurodevelopmental disorders such as schizophrenia. However, the mechanisms by which early damage leads to disease manifestation in later life remain largely unknown. Previously, we demonstrated that the activation of heat shock (HS) signaling can be utilized as a unique reporter to label the cells that undergo specific molecular/cellular changes upon exposure to environmental insults throughout the body. Since the activation of HS signaling is an acute and transient event, this approach was not intended for long-term tracing of affected cells after the activation has diminished. In the present study, we generated new reporter transgenic mouse lines as a novel tool to achieve systemic and long-term tracking of affected cells and their progeny. Methods The reporter transgenic mouse system was designed so that the activation of HS signaling through HS response element (HSE) drives flippase (FLPo)-flippase recognition target (FRT) recombination-mediated permanent expression of the red fluorescent protein (RFP), tdTomato. With a priority on consistent and efficient assessment of the reporter system, we focused on intraperitoneal (i.p.) injection models of high-dose, short prenatal exposure to alcohol (ethanol) and sodium arsenite (ethanol at 4.0 g/kg/day and sodium arsenite at 5.0 mg/kg/day, at embryonic day (E) 12 and 13). Long-term reporter expression was examined in the brain of reporter mice that were prenatally exposed to these insults. Electrophysiological properties were compared between RFP+ and RFP− cortical neurons in animals prenatally exposed to arsenite. Results We detected RFP+ neurons and glia in the brains of postnatal mice that had been prenatally exposed to alcohol or sodium arsenite. In animals prenatally exposed to sodium arsenite, we also detected reduced excitability in RFP+ cortical neurons. Conclusion The reporter transgenic mice allowed us to trace the cells that once responded to prenatal environmental stress and the progeny derived from these cells long after the exposure in postnatal animals. Tracing of these cells indicates that the impact of prenatal exposure on neural progenitor cells can lead to functional abnormalities in their progeny cells in the postnatal brain. Further studies using more clinically relevant exposure models are warranted to explore this mechanism.

Application of Lineage Tracing in Central Nervous System Development and Regeneration

“…Lineage tracing is an effective method for monitoring cells of interest (and their progeny) over the long term, and has been used to explore CNS diseases. To examine how early damage can lead to disease in later life, Mohammad et al generated transgenic reporter mouse lines as a novel tool for long-term, systemic tracking of cells (and their progeny) that sustained damage in the prenatal environmental [ 70 ]. They demonstrated that the long-term effects of prenatal exposure to environmental insult are mediated by altered regulation of key molecules, which can cause epigenetic modifications that may be inherited by progeny.…”

A Spacetime Odyssey of Neural Progenitors to Generate Neuronal Diversity

“…Genetic mutations and environmental insults may disrupt lineage development and impair neuronal diversification, which have been shown to predispose human beings to neurodevelopmental, neuropsychiatric, and neurodegenerative diseases [100][101][102]. Although previous studies have provided a wealth of knowledge on the molecular mechanisms of neural development, the genetic control of lineage specification in the developing brain remains underappreciated.…”

Activation of the anterior cingulate cortex ameliorates anxiety in a preclinical model of fetal alcohol spectrum disorders

“…Generation of the FASD mouse model was performed according to a previously published protocol [23,24], where pregnant CD-1 mice received an intraperitoneal injection (i.p.) of 25% ethanol (in PBS) solution at 4.0 g/kg bodyweight at embryonic day (E) 16 and 17.…”