title: Prenatal arsenic exposure alters REST/NRSF and microRNA regulators of embryonic neural stem cell fate in a sex-dependent manner.
abstract: Exposure to arsenic, a common environmental toxin found in drinking water, leads to a host of neurological pathologies. We have previously demonstrated that developmental exposure to a low level of arsenic (50ppb) alters epigenetic processes that underlie deficits in adult hippocampal neurogenesis leading to aberrant behavior. It is unclear if arsenic impacts the programming and regulation of embryonic neurogenesis during development when exposure occurs. The master negative regulator of neural-lineage, REST/NRSF, controls the precise timing of fate specification and differentiation of neural stem cells (NSCs). Early in development (embryonic day 14), we observed increased expression of Rest, its co-repressor, CoREST, and the inhibitory RNA binding/splicing protein, Ptbp1, and altered expression of mRNA spliced isoforms of Pbx1 that are directly regulated by these factors in the male brain in response to prenatal 50ppb arsenic exposure. These increases were concurrent with decreased expression of microRNA-9 (miR-9), miR-9*, and miR-124, all of which are REST/NRSF targets and inversely regulate Rest expression to allow for maturation of NSCs. Exposure to arsenic decreased the formation of neuroblasts in vitro from NSCs derived from male pup brains. The female response to arsenic was limited to increased expression of CoREST and Ptbp2, an RNA binding protein that allows for appropriate splicing of genes involved in the progression of neurogenesis. These changes were accompanied by increased neuroblast formation in vitro from NSCs derived from female pups. Unexposed male mice express transcriptomic factors to induce differentiation earlier in development compared to unexposed females. Thus, arsenic exposure likely delays differentiation of NSCs in males while potentially inducing precocious differentiation in females early in development. These effects are mitigated by embryonic day 18 of development. Arsenic-induced dysregulation of the regulatory loop formed by REST/NRSF, its target microRNAs, miR-9 and miR-124, and RNA splicing proteins, PTBP1 and 2, leads to aberrant programming of NSC function that is perhaps perpetuated into adulthood inducing deficits in differentiation we have previously observed.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM 87131, United States.
authors.forename: Christina R
authors.initials: CR
authors.lastname: Tyler
authors.affiliation: Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Labrecque
authors.affiliation: Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Solomon
authors.affiliation: Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States.
authors.forename: Xun
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Neurosciences, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States. Electronic address: aallan@salud.unm.edu.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Allan
mesh_terms: D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D002478:Cells, Cultured; D056970:Co-Repressor Proteins; D005260:Female; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D058953:Neural Stem Cells / Q000187:drug effects*; D055495:Neurogenesis / Q000187:drug effects; D038941:Polypyrimidine Tract-Binding Protein / Q000096:biosynthesis*; D000075062:Pre-B-Cell Leukemia Transcription Factor 1 / Q000096:biosynthesis; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism*; D012097:Repressor Proteins / Q000096:biosynthesis*; D012727:Sex Characteristics; D000099229:RE1-Silencing Transcription Factor
chemical_list: D001151:Arsenic; D056970:Co-Repressor Proteins; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D038941:Polypyrimidine Tract-Binding Protein; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor; C551804:MIRN9 microRNA, mouse; C540079:Mirn124 microRNA, mouse; C481797:Pbx1 protein, mouse; C573992:Ptbp1 protein, mouse; C429773:Ptbp2 protein, mouse; C485650:Rcor2 protein, mouse
keywords: Arsenic; Epigenetics; MicroRNA; Neural stem cell; REST; RNA binding protein