Activin A regulation under global hypoxia in developing mouse brain

Brackmann, Florian; Link, Andrea; Jung, Susan; Richter, Mandy; Zoglauer, Daniel; Walkinshaw, Gail; Alzheimer, Christian; Trollmann, Regina

doi:10.1016/j.brainres.2013.07.039

Cited by 11 publications

(11 citation statements)

References 34 publications

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“…400 ng of the purified PCR product was then used to synthesize digoxigenin‐labeled RNA probes according to the manufacturer's instructions (DIG RNA Labeling Kit (SP6/T7), Roche Applied Science). In situ hybridization was performed as previously described (Brackmann et al , ). Briefly, 14‐μm‐thick sections of back skin were post‐fixed with 4% PFA and hybridized to the Epgn antisense and sense probes at 60°C overnight.…”

Section: Methodsmentioning

confidence: 99%

Activation of Nrf2 in keratinocytes causes chloracne (MADISH)‐like skin disease in mice

et al. 2014

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The transcription factor Nrf2 is a key regulator of the cellular stress response, and pharmacological Nrf2 activation is a promising strategy for skin protection and cancer prevention. We show here that prolonged Nrf2 activation in keratinocytes causes sebaceous gland enlargement and seborrhea in mice due to upregulation of the growth factor epigen, which we identified as a novel Nrf2 target. This was accompanied by thickening and hyperkeratosis of hair follicle infundibula. These abnormalities caused dilatation of infundibula, hair loss, and cyst development upon aging. Upregulation of epigen, secretory leukocyte peptidase inhibitor (Slpi), and small proline-rich protein 2d (Sprr2d) in hair follicles was identified as the likely cause of infundibular acanthosis, hyperkeratosis, and cyst formation. These alterations were highly reminiscent to the phenotype of chloracne/“metabolizing acquired dioxin-induced skin hamartomas” (MADISH) patients. Indeed, SLPI, SPRR2, and epigen were strongly expressed in cysts of MADISH patients and upregulated by dioxin in human keratinocytes in an NRF2-dependent manner. These results identify novel Nrf2 activities in the pilosebaceous unit and point to a role of NRF2 in MADISH pathogenesis.

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Section: Methodsmentioning

confidence: 99%

Activation of Nrf2 in keratinocytes causes chloracne (MADISH)‐like skin disease in mice

et al. 2014

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“…The PCR product was gel-purified (MinElute Gel Extraction Kit, Qiagen), and 400 ng was used to synthesize digoxigenin-labeled RNA probes according to the manufacturer's instructions (DIG RNA Labeling Kit (SP6/T7), Roche). In situ hybridization was performed as previously described [25].…”

Section: In Situ Hybridizationmentioning

confidence: 99%

Kdm6b and Pmepa1 as Targets of Bioelectrically and Behaviorally Induced Activin A Signaling

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Kurinna²,

Havlicek

et al. 2015

Mol Neurobiol

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The transforming growth factor-β (TGF-β) family member activin A exerts multiple neurotrophic and protective effects in the brain. Activin also modulates cognitive functions and affective behavior and is a presumed target of antidepressant therapy. Despite its important role in the injured and intact brain, the mechanisms underlying activin effects in the CNS are still largely unknown. Our goal was to identify the first target genes of activin signaling in the hippocampus in vivo. Electroconvulsive seizures, a rodent model of electroconvulsive therapy in humans, were applied to C57BL/6J mice to elicit a strong increase in activin A signaling. Chromatin immunoprecipitation experiments with hippocampal lysates subsequently revealed that binding of SMAD2/3, the intracellular effectors of activin signaling, was significantly enriched at the Pmepa1 gene, which encodes a negative feedback regulator of TGF-β signaling in cancer cells, and at the Kdm6b gene, which encodes an epigenetic regulator promoting transcriptional plasticity. Underlining the significance of these findings, activin treatment also induced PMEPA1 and KDM6B expression in human forebrain neurons generated from embryonic stem cells suggesting interspecies conservation of activin effects in mammalian neurons. Importantly, physiological stimuli such as provided by environmental enrichment proved already sufficient to engender a rapid and significant induction of activin signaling concomitant with an upregulation of Pmepa1 and Kdm6b expression. Taken together, our study identified the first target genes of activin signaling in the brain. With the induction of Kdm6b expression, activin is likely to gain impact on a presumed epigenetic regulator of activity-dependent neuronal plasticity.

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“…Recently, our group presented data using an established model of acute systemic hypoxia 51,52 suggesting that neither in the adult nor the neonatal rodent brain even severe brain hypoxia was sufficient to stimulate cerebral activin A expression. 53 In addition, the previously observed activin A increases in moderate hypoxia 34 could not be confirmed either. 53 Therefore, hypoxia, if not accompanied by additional complicating factors such as ischemia, seizures, or traumatic tissue damage, does not seem to stimulate activin A expression in the developing and adult rodent brain.…”

Section: Activin a In Perinatal Brain Injurymentioning

confidence: 83%

“…53 In addition, the previously observed activin A increases in moderate hypoxia 34 could not be confirmed either. 53 Therefore, hypoxia, if not accompanied by additional complicating factors such as ischemia, seizures, or traumatic tissue damage, does not seem to stimulate activin A expression in the developing and adult rodent brain. 53 In addition, our investigation elucidated the age-dependent expression profile of activin A, its receptors (ActRIB, ActRIIA, and ActRIIB) and functional antagonists (follistatin and inhibin) at different stages of postnatal development in the rodent brain.…”

Section: Activin a In Perinatal Brain Injurymentioning

confidence: 83%

“…53 Therefore, hypoxia, if not accompanied by additional complicating factors such as ischemia, seizures, or traumatic tissue damage, does not seem to stimulate activin A expression in the developing and adult rodent brain. 53 In addition, our investigation elucidated the age-dependent expression profile of activin A, its receptors (ActRIB, ActRIIA, and ActRIIB) and functional antagonists (follistatin and inhibin) at different stages of postnatal development in the rodent brain. Starting on the first day of life up to adulthood, quite stable expression patterns of activin receptors with a specific increase of Act RIB were observed, whereas inhibin expression decreased over time (►Fig.…”

Section: Activin a In Perinatal Brain Injurymentioning

confidence: 98%

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Activin A in Perinatal Brain Injury

2015

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Activin A is a multifunctional growth and differentiation factor belonging to the transforming growth factor β (TGF-β) family. Growing evidence indicates its role as a neurotrophic factor and regulator of synaptic transmission as well as its functional importance in several types of cerebral injury. We recently described age-dependent expression of activin A and its regulation at the mRNA and protein level under different conditions of global hypoxia in the neonatal mouse brain. This review discusses the current knowledge of the function and regulation of activin A from human studies as well as from experimental models of brain injury focusing on acquired lesions of the developing rodent brain during the early stages of brain maturation.

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Activin A regulation under global hypoxia in developing mouse brain

Cited by 11 publications

References 34 publications

Activation of Nrf2 in keratinocytes causes chloracne (MADISH)‐like skin disease in mice

Activation of Nrf2 in keratinocytes causes chloracne (MADISH)‐like skin disease in mice

Kdm6b and Pmepa1 as Targets of Bioelectrically and Behaviorally Induced Activin A Signaling

Activin A in Perinatal Brain Injury

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