scholarly journals GABAB Receptor-Mediated Impairment of Intermediate Progenitor Maturation During Postnatal Hippocampal Neurogenesis of Newborn Rats

2021 ◽  
Vol 15 ◽  
Author(s):  
Charlotte Gustorff ◽  
Till Scheuer ◽  
Thomas Schmitz ◽  
Christoph Bührer ◽  
Stefanie Endesfelder
Keyword(s):  
Transcription Factors ◽  
Brain Development ◽  
Progenitor Cells ◽  
Neurodevelopmental Disorders ◽  
Hippocampal Neurogenesis ◽  
Receptor Blockade ◽  
Newborn Rats ◽  
Cell Counts ◽  
Postmitotic Neurons ◽  
Cgp 35348

The neurotransmitter GABA and its receptors assume essential functions during fetal and postnatal brain development. The last trimester of a human pregnancy and early postnatal life involves a vulnerable period of brain development. In the second half of gestation, there is a developmental shift from depolarizing to hyperpolarizing in the GABAergic system, which might be disturbed by preterm birth. Alterations of the postnatal GABA shift are associated with several neurodevelopmental disorders. In this in vivo study, we investigated neurogenesis in the dentate gyrus (DG) in response to daily administration of pharmacological GABAA (DMCM) and GABAB (CGP 35348) receptor inhibitors to newborn rats. Six-day-old Wistar rats (P6) were daily injected (i.p.) to postnatal day 11 (P11) with DMCM, CGP 35348, or vehicle to determine the effects of both antagonists on postnatal neurogenesis. Due to GABAB receptor blockade by CGP 35348, immunohistochemistry revealed a decrease in the number of NeuroD1 positive intermediate progenitor cells and a reduction of proliferative Nestin-positive neuronal stem cells at the DG. The impairment of hippocampal neurogenesis at this stage of differentiation is in line with a significantly decreased RNA expression of the transcription factors Pax6, Ascl1, and NeuroD1. Interestingly, the number of NeuN-positive postmitotic neurons was not affected by GABAB receptor blockade, although strictly associated transcription factors for postmitotic neurons, Tbr1, Prox1, and NeuroD2, displayed reduced expression levels, suggesting impairment by GABAB receptor antagonization at this stage of neurogenesis. Antagonization of GABAB receptors decreased the expression of neurotrophins (BDNF, NT-3, and NGF). In contrast to the GABAB receptor blockade, the GABAA receptor antagonization revealed no significant changes in cell counts, but an increased transcriptional expression of Tbr1 and Tbr2. We conclude that GABAergic signaling via the metabotropic GABAB receptor is crucial for hippocampal neurogenesis at the time of rapid brain growth and of the postnatal GABA shift. Differentiation and proliferation of intermediate progenitor cells are dependent on GABA. These insights become more pertinent in preterm infants whose developing brains are prematurely exposed to spostnatal stress and predisposed to poor neurodevelopmental disorders, possibly as sequelae of early disruption in GABAergic signaling.

Clock genes regulate neurogenic transcription factors, including NeuroD1, and the neuronal differentiation of adult neural stem/progenitor cells

2009 ◽  
Vol 54 (5-6) ◽  
pp. 277-285 ◽  
Author(s):  
Tomomi Kimiwada ◽  
Mikako Sakurai ◽  
Hiroki Ohashi ◽  
Shunsuke Aoki ◽  
Teiji Tominaga ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Progenitor Cells ◽  
Neuronal Differentiation ◽  
Clock Genes ◽  
Neural Stem Progenitor Cells

scholarly journals Regulation of the p75 neurotrophin receptor attenuates neuroinflammation and stimulates hippocampal neurogenesis in experimental Streptococcus pneumoniae meningitis

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Dandan Zhang ◽  
Shengnan Zhao ◽  
Zhijie Zhang ◽  
Danfeng Xu ◽  
Di Lian ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Streptococcus Pneumoniae ◽  
Proinflammatory Cytokines ◽  
Neuronal Apoptosis ◽  
Hippocampal Neurogenesis ◽  
Clinical Severity ◽  
Neurotrophin Receptor ◽  
Apoptosis And Necrosis

Abstract Background Streptococcus pneumoniae meningitis is a destructive central nervous system (CNS) infection with acute and long-term neurological disorders. Previous studies suggest that p75NTR signaling influences cell survival, apoptosis, and proliferation in brain-injured conditions. However, the role of p75NTR signaling in regulating pneumococcal meningitis (PM)-induced neuroinflammation and altered neurogenesis remains largely to be elucidated. Methods p75NTR signaling activation in the pathological process of PM was assessed. During acute PM, a small-molecule p75NTR modulator LM11A-31 or vehicle was intranasally administered for 3 days prior to S. pneumoniae exposure. At 24 h post-infection, clinical severity, histopathology, astrocytes/microglia activation, neuronal apoptosis and necrosis, inflammation-related transcription factors and proinflammatory cytokines/mediators were evaluated. Additionally, p75NTR was knocked down by the adenovirus-mediated short-hairpin RNA (shRNA) to ascertain the role of p75NTR in PM. During long-term PM, the intranasal administration of LM11A-31 or vehicle was continued for 7 days after successfully establishing the PM model. Dynamic changes in inflammation and hippocampal neurogenesis were assessed. Results Our results revealed that both 24 h (acute) and 7, 14, 28 day (long-term) groups of infected rats showed increased p75NTR expression in the brain. During acute PM, modulation of p75NTR through pretreatment of PM model with LM11A-31 significantly alleviated S. pneumoniae-induced clinical severity, histopathological injury and the activation of astrocytes and microglia. LM11A-31 pretreatment also significantly ameliorated neuronal apoptosis and necrosis. Moreover, we found that blocking p75NTR with LM11A-31 decreased the expression of inflammation-related transcription factors (NF-κBp65, C/EBPβ) and proinflammatory cytokines/mediators (IL-1β, TNF-α, IL-6 and iNOS). Furthermore, p75NTR knockdown induced significant changes in histopathology and inflammation-related transcription factors expression. Importantly, long-term LM11A-31 treatment accelerated the resolution of PM-induced inflammation and significantly improved hippocampal neurogenesis. Conclusion Our findings suggest that the p75NTR signaling plays an essential role in the pathogenesis of PM. Targeting p75NTR has beneficial effects on PM rats by alleviating neuroinflammation and promoting hippocampal neurogenesis. Thus, the p75NTR signaling may be a potential therapeutic target to improve the outcome of PM.

scholarly journals The Most Important Transcriptional Factors of Osteoblastogenesis

2010 ◽  
Vol 2 (1) ◽  
pp. 17-28 ◽  
Author(s):  
Malgorzata Witkowska-Zimny ◽  
Edyta Wrobel ◽  
Jacek Przybylski
Keyword(s):  
Transcription Factors ◽  
Molecular Biology ◽  
Bone Formation ◽  
Progenitor Cells ◽  
Transcriptional Factors ◽  
Differentiated Cells ◽  
Key Issues ◽  
Genetic Level

SummaryOne of the key issues of organogenesis is the understanding of mechanisms underlying the differentiation of progenitor cells into more specialized cells of individual tissues. Recent transcriptomic and proteomic approaches of molecular biology have led to the identification of several factors and mechanisms regulating morphogenesis at the genetic level which affect the function of already differentiated cells. In the last few years, several reports about osteoblastogenesis have been published. This review presents recent findings on the role of the most important transcription factors supporting bone formation.

scholarly journals Canonical Wnt-signaling modulates the tempo of dendritic growth of adult-born hippocampal neurons

2020 ◽  
Author(s):  
Jana Heppt ◽  
Marie-Theres Wittmann ◽  
Jingzhong Zhang ◽  
Daniela Vogt-Weisenhorn ◽  
Nilima Prakash ◽  
...  
Keyword(s):  
Young Adult ◽  
Wnt Signaling ◽  
Progenitor Cells ◽  
Dendritic Growth ◽  
Functional Integration ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Canonical Wnt Signaling ◽  
Adult Born Neurons ◽  
Canonical Wnt

AbstractIn adult hippocampal neurogenesis neural stem/progenitor cells generate new dentate granule neurons that contribute to hippocampal plasticity. The establishment of a morphologically defined dendritic arbor is central to the functional integration of adult-born neurons. Here, we investigated the role of canonical Wnt/β-catenin-signaling in dendritogenesis of adult-born neurons. We show that canonical Wnt-signaling follows a biphasic pattern, with high activity in stem/progenitor cells, attenuation in early immature neurons, and re-activation during maturation, and demonstrate that the biphasic activity pattern is required for proper dendrite development. Increasing β-catenin-signaling in maturing neurons of young adult mice transiently accelerated dendritic growth, but eventually resulted in dendritic defects and excessive spine numbers. In middle-aged mice, in which protracted dendrite and spine development was paralleled by lower canonical Wnt-signaling activity, enhancement of β-catenin-signaling restored dendritic growth and spine formation to levels observed in young adult animals. Our data indicate that precise timing and strength of β-catenin-signaling is essential for the correct functional integration of adult-born neurons and suggest Wnt/β-catenin-signaling as a pathway to ameliorate deficits in adult neurogenesis during aging.

scholarly journals Regulation of the p75 Neurotrophin Receptor Attenuates Neuroinflammation and Stimulates Hippocampal Neurogenesis in Experimental Streptococcus Pneumoniae Meningitis

2021 ◽  
Author(s):  
Dandan Zhang ◽  
Shengnan Zhao ◽  
Zhijie Zhang ◽  
Danfeng Xu ◽  
Di Lian ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Streptococcus Pneumoniae ◽  
Cell Apoptosis ◽  
Neuronal Cell ◽  
Hippocampal Neurogenesis ◽  
Clinical Severity ◽  
Neurotrophin Receptor ◽  
Double Labeling

Abstract Background: Streptococcus pneumoniae meningitis is a destructive central nervous system (CNS) infection with acute and long-term neurological disorders. Compelling evidence provided by previous studies suggests that p75NTR signaling influences cell survival, apoptosis, and proliferation in brain-injured conditions. However, the role of p75NTR signaling in regulating pneumococcal meningitis (PM)-induced neuroinflammation and altered neurogenesis remains largely to be elucidated.Methods: p75NTR signaling activation in the pathological process of PM was assessed. During acute PM, a small-molecule p75NTR modulator LM11A-31 or vehicle was intranasally administered for 3 days prior to S.pneumoniae exposure. At 24h post-infection, clinical severity, histopathology, astrocytes/microglia activation, neuronal cell apoptosis and death, inflammation-related transcription factors and inflammatory factors were evaluated. Additionally, p75NTR was knocked down by the adenovirus-mediated short-hairpin RNA (shRNA) to ascertain the role of p75NTR in PM. During long-term PM, the intranasal administration of LM11A-31 or vehicle was continued for 7 days after successfully establishing the PM model. Hippocampal neurogenesis was evaluated by double-labeling immunofluorescence with EdU, DCX and NeuN. Results: Our results revealed that both 24h (acute) and 7,14,28day (long-term) groups of infected rats demonstrated increased p75NTR expression in the brain. During acute PM, modulation of p75NTR through pretreatment of PM model with LM11A-31 significantly alleviated S.pneumoniae-induced clinical severity, histopathological injury and the activation of astrocytes and microglia. LM11A-31 pretreatment also significantly ameliorated neuronal cell apoptosis and death. Moreover, we found that blocking p75NTR with LM11A-31 decreased the expression of inflammation-related transcription factors (NF-κBp65, C/EBPβ) and proinflammatory cytokine (IL-1β, TNF-α, IL-6 and iNOS) in the cortex and hippocampus. Furthermore, p75NTR knockdown induced significant changes in histopathology and inflammation-related transcription factors expression. Importantly, combined LM11A-31 adjuvant therapy significantly improved hippocampal neurogenesis.Conclusion: Our findings suggest that the p75NTR signaling plays an essential role in the pathogenesis of PM. Targeting p75NTR has benefit effects on PM rats by alleviating neuroinflammation and promoting hippocampal neurogenesis. Thus, the p75NTR signaling may be a potential therapeutic target to improve the outcome of PM.

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