Microarray analysis of neonatal rat anteroventral periventricular transcriptomes identifies the proapoptotic Cugbp2 gene as sex-specific and regulated by estradiol

Pino, Javier del; Krishnan, Sudha; Aggison, Leah K.; Adams, Hillary L.; Shrikant, M.M.; López-Giráldez, Francesc; Petersen, Sandra L.

doi:10.1016/j.neuroscience.2015.07.008

Cited by 10 publications

(6 citation statements)

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“…The birth and death of new cells are two of the mechanisms through which hormones modify the structure, connectivity, and chemical function of the developing and adult nervous systems (Pawluski et al, 2009; Del Pino Sans et al, 2015; Juraska & Willing, 2016), and numerous studies have found that motherhood alters forebrain cytogenesis as well as cell death (Bridges & Grattan, 2003; Erbil et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

Motherhood and infant contact regulate neuroplasticity in the serotonergic midbrain dorsal raphe

Holschbach

Lonstein

2017

Psychoneuroendocrinology

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The adult brain shows remarkable neuroplasticity in response to hormones and the socioemotional modifications that they influence. In females with reproductive and maternal experience, this neuroplasticity includes the birth and death of new and existing cells in several forebrain regions involved in maternal caregiving and postpartum affective state. Such plasticity in midbrain sites critical for these processes has never been examined, though. Visualizing bromodeoxyuridine (BrdU) to label mitotic cells, l NeuroD for neuronal precursors, and TUNEL to identify dying cells, we found that the midbrain dorsal raphe nucleus (DR, the source of most ascending serotoninergic projections) exhibited significant neuroplasticity in response to motherhood. Specifically, BrdU analyses revealed that DR newborn cell survival (but not proliferation) was regulated by reproductive state, such that cells born early postpartum were less likely to survive compared to cells born during late pregnancy. Many of the surviving cells in the DR were NeuN immunoreactive, suggesting a neuronal phenotype. Similarly, late postpartum rats had fewer NeuroD-immunoreactive DR cells than early postpartum rats. Maternal experience contributed to the late postpartum reduction in DR newborn cell survival because removing the litter at parturition increased cell survival and reduced cell death. Unlike cytogenesis in the maternal hippocampus, which is reduced by circulating glucocorticoids, DR newborn cell survival was unaffected by postpartum adrenalectomy. These effects of reproductive state and motherhood on DR plasticity were associated with concurrent changes in DR levels of serotonin's precursor, 5-HTP, and its metabolite, 5-HIAA. Our results demonstrate for the first time that cytogenesis occurs in the midbrain DR of any adult mammal, that DR plasticity is influenced by female reproductive state and maternal experience, and that this plasticity is accompanied by changes in DR serotonergic function. Because serotonin is critical for postpartum caregiving behaviors and maternal affective state, neuroplastic changes in the DR may contribute to the neurochemical changes necessary for successful motherhood.

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Section: Introductionmentioning

confidence: 99%

Motherhood and infant contact regulate neuroplasticity in the serotonergic midbrain dorsal raphe

Holschbach

Lonstein

2017

Psychoneuroendocrinology

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“…High-throughput studies investigating the transcriptomic responses to estradiol in the AVPV+ or ARH+ have focused on the perinatal period [ 33 , 34 ], exposure to endocrine disrupting chemicals during prepuberty [ 35 ], or on the ARH exclusively [ 22 ]. The current study is the first high-throughput analysis of the transcriptomic responses to estradiol in the adult female rat AVPV and ARH regions.…”

Section: Discussionmentioning

confidence: 99%

RNA-sequencing of AVPV and ARH reveals vastly different temporal and transcriptomic responses to estradiol in the female rat hypothalamus

et al. 2021

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In females, estrogens have two main modes of action relating to gonadotropin secretion: positive feedback and negative feedback. Estrogen positive and negative feedback are controlled by different regions of the hypothalamus: the preoptic area/anterior portion (mainly the anteroventral periventricular nucleus, AVPV) of the hypothalamus is associated with estrogen positive feedback while the mediobasal hypothalamus (mainly the arcuate nucleus of the hypothalamus, ARH), is associated with estrogen negative feedback. In this study, we examined the temporal pattern of gene transcription in these two regions following estrogen treatment. Adult, ovariectomized, Long Evans rats received doses of estradiol benzoate (EB) or oil every 4 days for 3 cycles. On the last EB priming cycle, hypothalamic tissues were dissected into the AVPV+ and ARH+ at 0 hrs (baseline/oil control), 6 hrs, or 24 hrs after EB treatment. RNA was extracted and sequenced using bulk RNA sequencing. Differential gene analysis, gene ontology, and weighted correlation network analysis (WGCNA) was performed. Overall, we found that the AVPV+ and ARH+ respond differently to estradiol stimulation. In both regions, estradiol treatment resulted in more gene up-regulation than down-regulation. S100g was very strongly up-regulated by estradiol in both regions at 6 and 24 hrs after EB treatment. In the AVPV+ the highest number of differentially expressed genes occurred 24 hrs after EB. In the ARH+, the highest number of genes differentially expressed by EB occurred between 6 and 24 hrs after EB, while in the AVPV+, the fewest genes changed their expression between these time points, demonstrating a temporal difference in the way that EB regulates transcription these two areas. Several genes strongly implicated in gonadotropin release were differentially affected by estradiol including Esr1, encoding estrogen receptor-α and Kiss1, encoding kisspeptin. As an internal validation, Kiss1 was up-regulated in the AVPV+ and down-regulated in the ARH+. Gene network analysis revealed the vastly different clustering of genes modulated by estradiol in the AVPV+ compared with the ARH+. These results indicate that gene expression in these two hypothalamic regions have specific responses to estradiol in timing and direction.

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“…To explore in greater detail the molecular mechanisms underlying the sex difference in AVPV cell death in rats, Petersen and colleagues used targeted apoptosis microarrays and whole transcriptome analysis (Del Pino Sans et al, 2015; Krishnan et al, 2009). The microarrays identified a pathway that is important for controlling cell death in the immune system as sex-specifically active in the AVPV of rats; the tumor necrosis factor α receptor 2 (TNFαR2)/nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) cell survival pathway is more active in AVPV of neonatal females, likely because an inhibitor of this pathway is highly expressed in males (Krishnan et al, 2009).…”

Section: Cellular Bases Of Sex Differencesmentioning

confidence: 99%

“…The microarrays identified a pathway that is important for controlling cell death in the immune system as sex-specifically active in the AVPV of rats; the tumor necrosis factor α receptor 2 (TNFαR2)/nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) cell survival pathway is more active in AVPV of neonatal females, likely because an inhibitor of this pathway is highly expressed in males (Krishnan et al, 2009). In the transcriptome analysis, they found higher expression of the gene CUG triplet repeat, RNA binding protein 2 ( Cugbp2 ) in the AVPV of newborn male rats, and expression of this gene was increased in AVPV of newborn females 18 hours after estradiol treatment (Del Pino Sans et al, 2015). As Cugbp2 has been implicated in promoting cell death in other systems, this may be part of the molecular mechanism responsible for defeminizing AVPV in males.…”

Section: Cellular Bases Of Sex Differencesmentioning

confidence: 99%

“…Although the effect was highly statistically significant, the methylation status of only a minority of the genes that were affected by neonatal testosterone treatment of females (36% and 47% for the BNST/POA and striatum, respectively) also differed in methylation between normal males and females. At the transcriptome level, Del Pino Sans (2015) recently found 89 genes that were expressed at different levels in the AVPV of neonatal male and female rats, but > 300 genes that were significantly altered by neonatal estradiol treatment of females. More troubling, there were only 6 genes in common between the two lists!…”

Section: Uncomfortable Revelations About Our Favorite Models Of Sementioning

confidence: 99%

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Cellular and molecular mechanisms of sexual differentiation in the mammalian nervous system

Forger

Strahan

Castillo‐Ruiz

2016

Frontiers in Neuroendocrinology

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Neuroscientists are likely to discover new sex differences in the coming years, spurred by the National Institutes of Health initiative to include both sexes in preclinical studies. This review summarizes the current state of knowledge of the cellular and molecular mechanisms underlying sex differences in the mammalian nervous system, based primarily on work in rodents. Cellular mechanisms examined include neurogenesis, migration, the differentiation of neurochemical and morphological cell phenotype, and cell death. At the molecular level we discuss evolving roles for epigenetics, sex chromosome complement, the immune system, and newly identified cell signaling pathways. We review recent findings on the role of the environment, as well as genome-wide studies with some surprising results, causing us to rethink often-used models of sexual differentiation. We end by pointing to future directions, including an increased awareness of the important contributions of tissues outside of the nervous system to sexual differentiation of the brain.

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Microarray analysis of neonatal rat anteroventral periventricular transcriptomes identifies the proapoptotic Cugbp2 gene as sex-specific and regulated by estradiol

Cited by 10 publications

References 58 publications

Motherhood and infant contact regulate neuroplasticity in the serotonergic midbrain dorsal raphe

Motherhood and infant contact regulate neuroplasticity in the serotonergic midbrain dorsal raphe

RNA-sequencing of AVPV and ARH reveals vastly different temporal and transcriptomic responses to estradiol in the female rat hypothalamus

Cellular and molecular mechanisms of sexual differentiation in the mammalian nervous system

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