FKBP51 in glutamatergic forebrain neurons promotes early life stress inoculation in female mice via a Tcf4-mediated pathway
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ABSTRACT:
PROVIDER: PRJNA1079744 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR28069069_1.fastq.gz | Fastqsanger.gz | |||
| SRR28069069_2.fastq.gz | Fastqsanger.gz | |||
| SRR28069070_1.fastq.gz | Fastqsanger.gz | |||
| SRR28069070_2.fastq.gz | Fastqsanger.gz |
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Project description:Early life stress (ELS) has often been described as a risk factor for developing psychiatric disease. However, moderate exposure to ELS can also lead to stress inoculation and consequently adaptive changes on brain and behavior. Moreover, the FKBP5 gene, encoding the FKBP51 co-chaperone, has been associated with an increased risk for developing psychiatric disorders, specifically in interaction with ELS exposure. However, the underlying mechanisms behind the interaction of FKBP51 and moderate ELS exposure are still not completely understood and particularly data in the female sex are scarce. In this study, the contribution of FKBP51 in glutamatergic forebrain neurons to the long-term consequences of moderate ELS was investigated in both sexes, by using the Fkbp5Nex conditional knockout line. In female wild-type Fkbp5lox/lox mice, ELS exposure led to an anxiolytic phenotype and improved memory performance in a stressful context, however this ELS effect was absent in in Fkbp5Nexx wild-type mice. Interactive effects of FKBP51 in glutamatergic forebrain neurons and moderate ELS exposure in female mice were also reflected on brain volume of different cortical regions, the subiculum and white matter structures. Furthermore, interactive effects were observed for structural and electrophysiological properties of CA1 pyramidal neurons of the dorsal hippocampus. RNA sequencing of the hippocampus revealed the transcription factor 4 (TCF4) as a potential regulator of these interactive effects. Cre-dependent viral overexpression of TCF4 in female Nex-Cre mice led to similar beneficial effects on behavior as the moderate ELS exposure. Taken together, this study shows that FKBP51 in glutamatergic forebrain neurons mediates adaptive effects of moderate ELS exposure on emotional regulation, cognitive behavior and neuronal structure and function. Moreover, it proposes TCF4 as an underlying target that drives the FKBP51-mediated effects of moderate ELS on brain and behavior.
2024-02-26 | GSE256468 | GEO
Project description:Mental health disorders often arise as a combination of environmental and genetic factors. The FKBP5 gene, encoding the GR co-chaperone FKBP51, has been uncovered as a key genetic risk factor for stress related illness. However, the exact cell type and region-specific mechanisms by which FKBP51 contributes to stress resilience or susceptibility processes remain to be unravelled. FKBP51 functionality is known to interact with the environmental risk factors age and sex, but so far data on behavioral, structural and molecular consequences of these interactions are still largely unknown. Here we report the cell type- and sex-specific contribution of FKBP51 to stress susceptibility and resilience mechanisms under the high-risk environmental conditions of an older age, by using two conditional knockout models within glutamatergic (Fkbp5Nex) and GABAergic (Fkbp5Dlx) neurons of the forebrain. Specific manipulation of Fkbp5 in these two cell types led to opposing effects on behavior, brain structure and gene expression profiles in a highly sex-dependent fashion. The results emphasize the role of FKBP51 as a key player in stress-related illness and the need for more targeted and sex-specific treatment strategies.
2023-05-16 | GSE232460 | GEO
Project description: Not available
| S-EPMC11912546 | biostudies-literature
Project description:We report the data generated upon knockdown of TCF4 in hiPSC-derived neural progenitor cells and glutamatergic neurons.
2019-09-17 | GSE128333 | GEO
Project description:Mutations in PARK15, which encodes for the F-box protein FBXO7 have been associated with Parkinsonian Pyramidal syndrome, a rare and complex movement disorder with Parkinsonian symptoms, pyramidal tract signs and juvenile onset. Our previous study showed that systemic loss of Fbxo7 in mice causes motor defects and premature death. We have also demonstrated that FBXO7 has a crucial role in neurons as the specific deletion in tyrosine hydroxylase-positive or glutamatergic forebrain neurons leads to late-onset or early-onset motor dysfunction, respectively. In this study, we examined NEXCre; Fbxo7fl/fl mice, in which Fbxo7 was specifically deleted in glutamatergic projection neurons. The effects of FBXO7 deficiency on striatal integrity were investigated with HPLC and histological analyses. NEX-Cre;Fbxo7fl/fl mice revealed an increase in striatal dopamine concentrations, changes in the glutamatergic, GABAergic and dopaminergic pathways, astrogliosis and microgliosis and little or no neuronal loss in the striatum. To determine the effects on the integrity of the synapse, we purified synaptic membranes, subjected them to quantitative mass spectrometry analysis and found alterations in the complement system, endocytosis and exocytosis pathways. These neuropathological changes coincide with alterations in spontaneous home cage behavior. Taken together, our findings suggest that FBXO7 is crucial for corticostriatal projections and the synaptic integrity of the striatum, and consequently for proper motor control.
2023-09-18 | PXD044119 | Pride
Project description:Sex-Specific and Opposed Effects of FKBP51 in Glutamatergic and GABAergic Neurons: Implications for Stress Susceptibility and Resilience
| PRJNA972070 | ENA
Project description:The bHLH transcription factor TCF4 plays an important role in neurodevelopment highlighted by its association with schizophrenia and Pitt-Hopkins-Syndrome. Here we demonstrate that TCF4 function is essential for forebrain commissure formation in mice. Single-cell RNA sequencing of TCF4 knockout neocortices revealed dysregulation of multiple gene regulatory networks. We provide evidence that TCF4 controls the underlying regulons by interaction with the regulators, transcription factors surprisingly not belonging to the known canonical interactors of the bHLH family. In-depth analysis of the interplay between TCF4 and SOX11 showed a synergistic effect on commissural formation. Mice haploinsufficient for Sox11 or Tcf4 showed no commissural phenotype or only a mild callosal shortening, respectively, whereas Tcf4/Sox11 double haploinsufficient mice display aggravated corpus callosum dysgenesis and anterior commissure agenesis. Moreover, TCF4 and SOX11 synergistically induce the expression of common target genes. Collectively, these findings illuminate how TCF4 dysregulation influences brain development and contributes to neurodevelopmental diseases.
2021-07-04 | GSE147247 | GEO
Project description:FKBP51 is an immunophilin with a relevant role in sustaining cancer cell growth and aggressiveness, particularly in melanoma. Thanks to its scaffold and isomerase activities, mediated by its TPR and FK1 domains, respectively, FKBP51 participates in several signaling pathways. Akt is a serine-threonine kinase that is constitutively active in many tumors with a role in cancer growth and resistance. FKBP51 forms a complex with Akt and PH-domain leucine-rich repeat protein phosphatase (PHLPP), which is reported to deactivate Akt. The effect of FKBP51 on Akt activation is far from being fully elucidated and opposite data emerge from literature. We recently identified a spliced FKBP51 isoform. In this paper, we interrogated the two FKBP51 isoforms in the regulation of Akt activation and the underlying mechanisms. Our finding shows that the pAkt levels were upregulated by the canonical but not the spliced FKBP51. We show that the TPR domain mediates Akt-K63-ubiquitination, an essential aspect of Akt activation. The spliced FKBP51s, lacking such domain, could not link K63-Ub residues to Akt. Unexpectedly, PHLPP silencing did not foster phosphorylation of Akt, and its overexpression even induced phosphorylation of Akt. Our finding shows that PHLPP stabilizes levels of the E3-ubiquitin ligase TRAF6, a known FKBP51 interactor. We observed an increased K63-ubiquitination of Akt upon PHLPP overexpression. A mass spectrometry-based proteome profile of melanoma cells highlighted a relevant role for such phosphatase in improving oncogenic hallmarks, first, cell proliferation. In conclusion, we show that canonical FKBP51 promotes Akt activation by serving as a scaffold to build the macro complex deputed to Akt ubiquitination and phosphorylation. The short FKBP51 isoform, even if it retains the ability to bind to Akt, cannot support Akt phosphorylation, being unable to engage K63-ubiquitin.
2023-03-11 | PXD033828 | Pride
Project description:Early life adversity (ELA) is a major risk factor for psychiatric disorders, but targeted preventative strategies are lacking due to poor mechanistic insight. The FKBP51 protein, a co-chaperone of the glucocorticoid receptor, is a key mediator of stress vulnerability. We tested if pharmacological inhibition of FKBP51 with the selective inhibitor SAFit2 prevents the long-term consequences of ELA. Mice exposed to ELA exhibited persistent deficits in social behavior, manifesting as social subordination in adolescence and adulthood. Early-life SAFit2 treatment fully rescued these ELA-induced behavioral impairments. Transcriptional profiling across six stress-relevant brain regions revealed that SAFit2 normalized ELA-driven gene expression changes, particularly in the medial prefrontal cortex and nucleus accumbens. Functional analysis showed the rescue converged on immunoregulatory and neuroactive ligand-receptor signaling pathways. Our findings establish FKBP51 as a critical pharmacological target for reversing the lasting impact of early life adversity on brain function, offering a path toward preventative treatment for ELA-related psychopathology.
2026-07-15 | GSE318028 | GEO
Project description:Chronic pain affects 20-30% of the population and imposes a significant socio-economic burden as it is often accompanied by substantial emotional comorbidities such as anxiety and depression. Yet, the mechanisms underlying the interactions between the sensory and emotional aspects of chronic pain remain poorly understood. Here, we investigated the role of FKBP51, a regulator of the stress response, in mediating both sensory and emotional symptoms of chronic pain. Inhibition of FKBP51, via genetic deletion or pharmacological blockade, in persistent joint pain reduced fast-onset sensory, functional and activity-related symptoms, as well as late anxio-depressive comorbidities. FKBP51 inhibition after the establishment of the hypersensitive state provided only temporary symptoms relief, while acute inhibition at disease onset protected from the full development of sensory and anxio-depressive symptoms for up to 6 months. Our results also indicated that early pain symptoms could predict the late sensory and emotional outcomes of chronic pain. RNA sequencing of spinal cord tissue revealed that late FKBP51 inhibition transiently altered nociceptive genes associated with mechanical hypersensitivity. In contrast, early inhibition persistently downregulated the Naaa gene, a key regulator of the transition to chronic pain, and reorganized spinal cilia. Our results indicate that early FKBP51 inhibition after injury can persistently reduce chronic pain and prevent the onset of associated emotional comorbidities by modulating critical spinal neurobiological pathways that play pivotal roles in the transition to chronic pain.
2025-10-14 | GSE293520 | GEO