Estradiol Meets Notch Signaling in Developing Neurons

Arévalo, María Ángeles; Ruiz-Palmero, Isabel; Simon-Areces, Julia; Acaz‐Fonseca, Estefanía; Azcoitia, Íñigo; Garcia-Segura, Luis Miguel

doi:10.3389/fendo.2011.00021

Cited by 7 publications

(14 citation statements)

References 57 publications

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“…In addition, in the vertebrate brain, aromatase, which catalyzes estrogen synthesis, is expressed by neural progenitor cells (37) and regulates neural progenitor cell proliferation (38). E 2 has been speculated to lower Notch signaling during brain development, resulting in Ngn3-dependent neural cell differentiation (18). Of note, certain variants of the NGN3 gene are associated with more severe hyperglycemia in men but not in women with diabetes (39).…”

Section: Discussionmentioning

confidence: 99%

“…Because Ngn3 gene expression is regulated by estrogen in developing neurons (18) and was reduced by ERa inactivation in PDL pancreas ( Figs. 2A and 3D), we examined the Ngn3 mRNA level in E15.5 pancreas of ERa +/+ and ERa 2/2 embryos and found it significantly decreased in ERa +/+ embryos that received TAM and in untreated ERa 2/2 embryos compared with ERa +/+ control embryos (Fig.…”

Section: Progenitors In the Embryonic Pancreasmentioning

confidence: 99%

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Estrogen Receptor α Regulates β-Cell Formation During Pancreas Development and Following Injury

et al. 2015

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Identifying pathways for b-cell generation is essential for cell therapy in diabetes. We investigated the potential of 17b-estradiol (E 2 ) and estrogen receptor (ER) signaling for stimulating b-cell generation during embryonic development and in the severely injured adult pancreas. E 2 concentration, ER activity, and number of ERa transcripts were enhanced in the pancreas injured by partial duct ligation (PDL) along with nuclear localization of ERa in b-cells. PDL-induced proliferation of b-cells depended on aromatase activity. The activation of Neurogenin3 (Ngn3) gene expression and b-cell growth in PDL pancreas were impaired when ERa was turned off chemically or genetically (ERa 2/2 ), whereas in situ delivery of E 2 promoted b-cell formation. In the embryonic pancreas, b-cell replication, number of Ngn3 + progenitor cells, and expression of key transcription factors of the endocrine lineage were decreased by ERa inactivation. The current study reveals that E 2 and ERa signaling can drive b-cell replication and formation in mouse pancreas.Decreased functional b-cell mass is the major cause for hyperglycemia in diabetes. Restoration of the endogenous b-cell mass as a therapeutic strategy, however, requires a better understanding of signaling pathways that control b-cell growth and differentiation. Embryonic b-cells are generated by a developmental program executed through the timed action of a number of key transcription factors among which Neurogenin3 (Ngn3) is key for endocrine specification. Ngn3 + cells delaminate from pancreatic epithelium, are mitotically quiescent, and give rise to endocrine cells. Ngn3 cells appear maximally competent for driving b-cell formation at embryonic day (E) 14.5. Formed b-cells expand through self-replication, already evident at E18.5, and continue into early postnatal life (1). Also in adult mice with severely injured pancreas by partial duct ligation (PDL), Ngn3 + cells are generated near duct epithelium and can differentiate into b-cells (2). b-Cells are vastly generated through replication in PDL (3,4), but some derive from acinar (5) and duct (6) cells, apparently through an Ngn3 + stage (2,5) as in embryonic pancreas. How the numbers of Ngn3 + endocrine progenitors and replicating b-cells are controlled in the embryonic or mature pancreas is uncertain. Identifying factors that control these processes and manipulating them may be of therapeutic advantage. What is known is that 17b-estradiol (E 2 ) enhances b-cell survival and glycemic control in various animal models (7,8) by signaling through estrogen receptor (ER) a (8,9) and/or ERb (10).However, little is known about the importance of estrogen and ER signaling for b-cell proliferation and differentiation. So far, no in vivo effects on b-cell formation have been reported for the ER antagonist tamoxifen (TAM), although this compound is used to conditionally activate Cre recombinase activity (Cre ERT ) in genetic

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Section: Discussionmentioning

confidence: 99%

Section: Progenitors In the Embryonic Pancreasmentioning

confidence: 99%

Estrogen Receptor α Regulates β-Cell Formation During Pancreas Development and Following Injury

et al. 2015

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“…Fujimoto et al 2009;Imayoshi et al 2010). Of note, recent evidence suggests there is considerable interaction between Notch signaling and sex hormones including estradiol (Soares et al 2004;Arevalo et al 2011;Ruiz-Palmero et al 2011). Sex hormones are believed to contribute to the sexual differentiation of the brain that occurs in the second half of pregnancy (Bakker and Brock 2010) and are known to be potent modifiers of epigenetic status and transcription in the brain (Ghahramani et al 2014).…”

Section: à15mentioning

confidence: 99%

Methylomic trajectories across human fetal brain development

et al. 2015

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Epigenetic processes play a key role in orchestrating transcriptional regulation during development. The importance of DNA methylation in fetal brain development is highlighted by the dynamic expression of de novo DNA methyltransferases during the perinatal period and neurodevelopmental deficits associated with mutations in the methyl-CpG binding protein 2 (MECP2) gene. However, our knowledge about the temporal changes to the epigenome during fetal brain development has, to date, been limited. We quantified genome-wide patterns of DNA methylation at~400,000 sites in 179 human fetal brain samples (100 male, 79 female) spanning 23 to 184 d post-conception. We identified highly significant changes in DNA methylation across fetal brain development at >7% of sites, with an enrichment of loci becoming hypomethylated with fetal age. Sites associated with developmental changes in DNA methylation during fetal brain development were significantly underrepresented in promoter regulatory regions but significantly overrepresented in regions flanking CpG islands (shores and shelves) and gene bodies. Highly significant differences in DNA methylation were observed between males and females at a number of autosomal sites, with a small number of regions showing sex-specific DNA methylation trajectories across brain development. Weighted gene comethylation network analysis (WGCNA) revealed discrete modules of comethylated loci associated with fetal age that are significantly enriched for genes involved in neurodevelopmental processes. This is, to our knowledge, the most extensive study of DNA methylation across human fetal brain development to date, confirming the prenatal period as a time of considerable epigenomic plasticity.

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“…Notch receptor is activated by transmembrane ligands, such as Jagged and Delta. The activation of Notch receptor results in the cleavage of its intracellular domain, which is translocated to the cell nucleus and regulates the expression of different transcription factors, such as hairy and enhancer of split (Hes) 1 and 5 (Arevalo et al, 2011).…”

Section: Notch Signalingmentioning

confidence: 99%

Molecular mechanisms and cellular events involved in the neuroprotective actions of estradiol. Analysis of sex differences

Azcoitia

Barreto

García‐Segura

2019

Frontiers in Neuroendocrinology

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Estradiol, either from peripheral or central origin, activates multiple molecular neuroprotective and neuroreparative responses that, being mediated by estrogen receptors or by estrogen receptor independent mechanisms, are initiated at the membrane, the cytoplasm or the cell nucleus of neural cells. Estrogen-dependent signaling regulates a variety of cellular events, such as intracellular Ca 2+ levels, mitochondrial respiratory capacity, ATP production, mitochondrial membrane potential, autophagy and apoptosis. In turn, these molecular and cellular actions of estradiol are integrated by neurons and non-neuronal cells to generate different tissue protective responses, decreasing blood-brain barrier permeability, oxidative stress, neuroinflammation and excitotoxicity and promoting synaptic plasticity, axonal growth, neurogenesis, remyelination and neuroregeneration. Recent findings indicate that the neuroprotective and neuroreparative actions of estradiol are different in males and females and further research is necessary to fully elucidate the causes for this sex difference.

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Estradiol Meets Notch Signaling in Developing Neurons

Cited by 7 publications

References 57 publications

Estrogen Receptor α Regulates β-Cell Formation During Pancreas Development and Following Injury

Estrogen Receptor α Regulates β-Cell Formation During Pancreas Development and Following Injury

Methylomic trajectories across human fetal brain development

Molecular mechanisms and cellular events involved in the neuroprotective actions of estradiol. Analysis of sex differences

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