Journal
NEUROSCIENCE
Volume 412, Issue -, Pages 60-71Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuroscience.2019.05.044
Keywords
DNMT1; hypothalamus; neurogenesis; neurons; astrocytes; developmental programming
Categories
Funding
- National Institutes of Health [R01HD054751, R01DK081756]
- LA BioMed Research Committee Bridge and Institutional Use Grant Program [531230]
Ask authors/readers for more resources
Small-for-gestational age (SGA) human newborns have an increased risk of hyperphagia and obesity, as well as a spectrum of neurologic and neurobehavioral abnormalities. We have shown that the SGA hypothalamic (appetite regulatory site) neuroprogenitor cells (NPCs) exhibit reduced proliferation and neuronal differentiation. DNA methylation (DNA methyltransferase; DNMT1) regulates neurogenesis by maintaining NPC proliferation and suppressing premature differentiation. Once differentiation ensues, DNMT1 preferentially promotes neuronal and inhibits astroglial fate. We hypothesized that the programmed dysfunction of NPC proliferation and differentiation in SGA offspring is epigenetically mediated via DNMT1. Pregnant rats received either ad libitum food (Control) or were 50% food-restricted to create SGA offspring. Primary hypothalamic NPCs from 1 day old SGA and Controls newborns were cultured and transfected with nonspecific or DNMT1-specific siRNA. NPC proliferation and protein expression of specific markers of NPC (nestin), neuroproliferative transcription factor (Hes1), neurons (Tuj1) and astrocytes (GFAP) were determined. Under basal conditions, SGA NPCs exhibited decreased DNMT1 and reduced proliferation and differentiation, as compared to Controls. In both SGA and Controls, DNMT1 siRNA in complete media inhibited NPC proliferation, consistent with reduced expression of nestin and Hes1. In differentiation media, DNMT1 siRNA decreased expression of Tuj1 but increased GFAP. In vivo data replicated these findings. In SGA offspring, impaired neurogenesis is epigenetically mediated, in part, via reduction in DNMT1 expression and suppression of Hes1 resulting in NPC differentiation. It is likely that the maturation of regions beyond the hypothalamus (e.g., cerebral cortex, hippocampus) may be impacted, contributing to poor cognitive and neurobehavioral competency in SGA offspring. (C) 2019 Published by Elsevier Ltd on behalf of IBRO.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available