Age, but Not Sex, Modulates Foxp3 Expression in the Rat Brain across Development

Taylor, Makenzlie R.; Roby, Clinton R.; Elziny, Soad; Duricy, Erin; Dyches, Tina Taylor; Bowers, J. Michael

doi:10.1016/j.neuroscience.2020.06.032

Cited by 6 publications

(4 citation statements)

References 78 publications

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“…In females, we identified the primary target as ADIPOQ, which in the brain is a known regulator of the neuron inflammation response (Bloemer et al, 2018), likely through control of FOXP3 and IL10 function. Importantly, FOXP3 is ubiquitously expressed in the brain with no observed sex differences (Taylor et al, 2020) and is a known transcription factor and repressor of the well-described memory-permissive NF-κB signaling pathway (Kim, 2009). IL10 is an anti-inflammatory cytokine that is one of the most important mechanisms involved in limiting neuroinflammation (Lobo-Silva et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Sex-Specific Linear Polyubiquitination Is a Critical Regulator of Contextual Fear Memory Formation

Musaus

Farrell

Navabpour

et al. 2021

Front. Behav. Neurosci.

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Strong evidence supports that protein ubiquitination is a critical regulator of fear memory formation. However, as this work has focused on protein degradation, it is currently unknown whether polyubiquitin modifications that are independent of the proteasome are involved in learning-dependent synaptic plasticity. Here, we present the first evidence that atypical linear (M1) polyubiquitination, the only ubiquitin chain that does not occur at a lysine site and is largely independent of the proteasome, is critically involved in contextual fear memory formation in the amygdala in a sex-specific manner. Using immunoblot and unbiased proteomic analyses, we found that male (49) and female (14) rats both had increased levels of linear polyubiquitinated substrates following fear conditioning, though none of these protein targets overlapped between sexes. In males, target protein functions involved cell junction and axonal guidance signaling, while in females the primary target was Adiponectin A, a critical regulator of neuroinflammation, synaptic plasticity, and memory, suggesting sex-dependent functional roles for linear polyubiquitination during fear memory formation. Consistent with these increases, in vivo siRNA-mediated knockdown of Rnf31, an essential component of the linear polyubiquitin E3 complex LUBAC, in the amygdala impaired contextual fear memory in both sexes without affecting memory retrieval. Collectively, these results provide the first evidence that proteasome-independent linear polyubiquitination is a critical regulator of fear memory formation, expanding the potential roles of ubiquitin-signaling in learning-dependent synaptic plasticity. Importantly, our data identify a novel sex difference in the functional role of, but not a requirement for, linear polyubiquitination in fear memory formation.

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Section: Discussionmentioning

confidence: 99%

Sex-Specific Linear Polyubiquitination Is a Critical Regulator of Contextual Fear Memory Formation

Musaus

Farrell

Navabpour

et al. 2021

Front. Behav. Neurosci.

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“…Moreover, a meta‐analysis of GWAS found an overlap in regions implicated in schizophrenia and ASD in FOXP3 and ATPase plasma membrane Ca2+ transporting 2 ( ATP2B2 ) genes (The Autism Spectrum Disorders Working Group of the Psychiatric Genomics Consortium, 2017). This is particularly interesting because FOXP3 is an essential regulator of the immune system (Taylor et al, 2020), and ATP2B2 regulates intracellular calcium homeostasis, necessary for appropriate synaptic connections (Yang et al, 2013).…”

Section: Ndd‐associated Multifactorial Disordersmentioning

confidence: 99%

Transcription factors in neurodevelopmental and associated psychiatric disorders: A potential convergence for genetic and environmental risk factors

Santos-Terra

Deckmann

Fontes-Dutra

et al. 2021

Intl J of Devlp Neuroscience

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Neurodevelopmental disorders (NDDs) are a heterogeneous and highly prevalent group of psychiatric conditions marked by impairments in the nervous system. Their onset occurs during gestation, and the alterations are observed throughout the postnatal life. Although many genetic and environmental risk factors have been described in this context, the interactions between them challenge the understanding of the pathways associated with NDDs. Transcription factors (TFs)—a group of over 1,600 proteins that can interact with DNA, regulating gene expression through modulation of RNA synthesis—represent a point of convergence for different risk factors. In addition, TFs organize critical processes like angiogenesis, blood‐brain barrier formation, myelination, neuronal migration, immune activation, and many others in a time and location‐dependent way. In this review, we summarize important TF alterations in NDD and associated disorders, along with specific impairments observed in animal models, and, finally, establish hypotheses to explain how these proteins may be critical mediators in the context of genome‐environment interactions.

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“…The levels of Foxp3 protein in PNS were low in the embryo, increased throughout life and reached maximum levels in adulthood. The patterns observed for both PNS and CNS were similar in men and women at all stages of development [ 57 ]. It is difficult to interpret unambiguously the phenomenon of Foxp3 levels dropping in patients with depression.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory versus Anti-Inflammatory Profiles in Major Depressive Disorders—The Role of IL-17, IL-21, IL-23, IL-35 and Foxp3

Gałecka

Bliźniewska-Kowalska

Orzechowska

et al. 2021

JPM

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Background: The authors of this research study intended to verify whether there are any changes in gene expression in depressed patients without coexisting inflammatory diseases for selected immune-inflammatory factors that are particularly important in autoimmune disease pathogenesis (IL-17, IL-21, IL-23, IL-35, Foxp3). Methods: The study was carried out on a group of 190 patients with depression and 100 healthy volunteers. The severity of depressive symptoms was assessed using the Hamilton Depression Scale. RT-PCR was used to evaluate mRNA expression and ELISA was used to measure protein expression of these genes. Results: The level of gene expression for IL-17, IL-21, IL-23, and IL-35 was substantially higher in the group of patients with depression compared to the control group. The mean mRNA expression of Foxp3 was considerably reduced in patients suffering from depressive disorders. There was a statistically significant correlation between the number of hospitalizations and the expression of specific inflammatory factors. Conclusions: Expression of specific inflammatory genes may be a factor in the etiopathogenesis of depressive disorders. The duration of the disease seems to be more important for the expression of the genes in question than the severity of depression. These cytokines may affect the metabolism of neurotransmitters and neuroendocrine functions in the brain as well as be a marker and a new potential therapeutic target for recurrent depressive disorders.

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Age, but Not Sex, Modulates Foxp3 Expression in the Rat Brain across Development

Cited by 6 publications

References 78 publications

Sex-Specific Linear Polyubiquitination Is a Critical Regulator of Contextual Fear Memory Formation

Sex-Specific Linear Polyubiquitination Is a Critical Regulator of Contextual Fear Memory Formation

Transcription factors in neurodevelopmental and associated psychiatric disorders: A potential convergence for genetic and environmental risk factors

Inflammatory versus Anti-Inflammatory Profiles in Major Depressive Disorders—The Role of IL-17, IL-21, IL-23, IL-35 and Foxp3

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