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. 2014 Jul 1;111(26):9639-44.
doi: 10.1073/pnas.1401203111. Epub 2014 Jun 16.

Targeted placental deletion of OGT recapitulates the prenatal stress phenotype including hypothalamic mitochondrial dysfunction

Christopher L Howerton  1 , Tracy L Bale  1
Affiliations

Targeted placental deletion of OGT recapitulates the prenatal stress phenotype including hypothalamic mitochondrial dysfunction

Christopher L Howerton et al. Proc Natl Acad Sci U S A. .

Abstract

Maternal stress is a key risk factor in neurodevelopmental disorders, which often have a sex bias in severity and prevalence. We previously identified O-GlcNAc transferase (OGT) as a placental biomarker in our mouse model of early prenatal stress (EPS), where OGT levels were lower in male compared with female tissue and were further decreased following maternal stress. However, the function of placental OGT in programming the developing brain has not been determined. Therefore, we generated a transgenic mouse with targeted placental disruption of Ogt (Pl-OGT) and examined offspring for recapitulation of the adult EPS phenotype. Pl-OGT hemizygous and EPS male placentas showed similar robust changes in gene expression patterns suggestive of an altered ability to respond to endocrine and inflammatory signals, supporting placental OGT as an important mediator of EPS effects. ChIP-Seq for the O-GlcNAc mark identified the 17 beta hydroxysteroid dehydrogenase-3 (Hsd17b3) locus in male EPS placentas, which correlated with a reduction in Hsd17b3 expression and concordant reduced testosterone conversion. Remarkably, Pl-OGT adult offspring had reduced body weights and elevated hypothalamic-pituitary-adrenal stress axis responsivity, recapitulating phenotypes previously reported for EPS males. Further, hypothalamic microarray gene-set enrichment analyses identified reduced mitochondrial function in both Pl-OGT and EPS males. Cytochrome c oxidase activity assays verified this finding, linking reduced placental OGT with critical brain programming. Together, these studies confirm OGT as in important placental biomarker of maternal stress and demonstrate the profound impact a single placental gene has on long-term metabolic and neurodevelopmental programming that may be related to an increased risk for neurodevelopmental disorders.

Keywords: 17b-HSD3; hypothalamus; mitochondria; neurodevelopment.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
EPS and genetically reduced OGT impacts placental biology. (A) Distribution of placental ChIP-seq peaks by chromatin modification and treatment. There is a marked reduction of O-GlcNAc (OG), but not H3K4me3 (H3), peaks with EPS. (B) Effect of chromatin state on placental gene expression by treatment. In control placentas, O-GlcNAc synergistically increases expression with H3K4me3, but the opposite is true in EPS placentas. (C) Hsd17b3, the enzyme that catalyzes the conversion of androstenedione to testosterone, has reduced O-GlcNAc occupancy at its locus and a marked reduction in gene expression in EPS placentas compared with control (C). (D) The reduction of Hsd17b3 expression in EPS placentas is correlated with an increase in androstenedione and reduction in testosterone. *Significant difference (by confidence interval inspection) between the groups.
Fig. 2.
Fig. 2.
Genetically reduced placental OGT recapitulates key features of the EPS phenotype. Both male (A) and female (B) mice that had genetically reduced placental OGT have a reduced bodyweights after weaning at 4 wk of age compared with WT littermates (n = 8 per genotype). There is a dose–response in this growth retardation with respect to the zygosity of the Ogt locus, observable in the female mice (B). (C and D) Mice with reduced placental OGT also had lower adiposity (as measured by gonadal fat pad weight) (C) and were shorter (as measured by tibial length) (D) compared with WT littermates. (E) Photograph of all possible genotypes of mice (XOGT-/Y, XWT/Y, XOGT-/XOGT-, XOGT-/XWT, XWT/XWT). Qualitative observations confirm a shorter leaner phenotype in adult mice that had genetically reduced placental OGT. (F) Genetically reduced placental OGT had no effect on anxiety-like behavior (as measured by time in the light within the light-dark box task; n = 8 per genotype). (G and H) Both male (G) and female (H) mice that had genetically reduced placental OGT have a dysregulated HPA response to a restraint stress compared with WT littermates (n = 8 per genotype). XOGT-/Y mice have a hyperresponsive HPA (the same direction as EPS males), whereas XOGT-/XOGT- and XOGT-/XWT have a hyporesponsive HPA (a phenotype not observed in EPS females). *Significant difference (by confidence interval inspection) between the groups.
Fig. 3.
Fig. 3.
Reduced placental OGT and EPS result in hypothalamic mitochondrial dysregulation. (A) Heat map of hypothalamic genes with significantly different levels of expression between XOGT-/Y (n = 6) and XWT/Y mice (n = 5). (B) Differences in gene-set expression values from the comparisons between either XOGT-/Y and XWT/Y (white bars; n = 6 or 5, respectively) or male control and EPS (gray bars; n = 6 per group) hypothalamic punches. Both XOGT-/Y and male EPS had a down-regulation of mitochondrion related gene sets compared with their respective controls. (C) Both EPS and XOGT-/Y mice had reduced CCO activity at postnatal day 2 compared with their controls (n = 6 per group). CCO is the rate-limiting step of oxidative phosphorylation within the mitochondria. Asterisks represent significant difference (by confidence interval inspection) between the groups.
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