scholarly journals Myocyte Enhancer Factor 2A (MEF2A) Defines Oxytocin-Induced Morphological Effects and Regulates Mitochondrial Function in Neurons

2020 ◽  
Vol 21 (6) ◽  
pp. 2200 ◽  
Author(s):  
Magdalena Meyer ◽  
Kerstin Kuffner ◽  
Julia Winter ◽  
Inga D. Neumann ◽  
Christian H. Wetzel ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Cellular Response ◽  
Autism Spectrum ◽  
Neuronal Morphology ◽  
Cellular Respiration ◽  
Morphological Alterations ◽  
Neurite Retraction ◽  
Upstream Regulator ◽  
Myocyte Enhancer Factor ◽  
Enhancer Factor

The neuropeptide oxytocin (OT) is a well-described modulator of socio-emotional traits, such as anxiety, stress, social behavior, and pair bonding. However, when dysregulated, it is associated with adverse psychiatric traits, such as various aspects of autism spectrum disorder (ASD). In this study, we identify the transcription factor myocyte enhancer factor 2A (MEF2A) as the common link between OT and cellular changes symptomatic for ASD, encompassing neuronal morphology, connectivity, and mitochondrial function. We provide evidence for MEF2A as the decisive factor defining the cellular response to OT: while OT induces neurite retraction in MEF2A expressing neurons, OT causes neurite outgrowth in absence of MEF2A. A CRISPR-Cas-mediated knockout of MEF2A and retransfection of an active version or permanently inactive mutant, respectively, validated our findings. We also identified the phosphatase calcineurin as the main upstream regulator of OT-induced MEF2A signaling. Further, MEF2A signaling dampens mitochondrial functioning in neurons, as MEF2A knockout cells show increased maximal cellular respiration, spare respiratory capacity, and total cellular ATP. In summary, we reveal a central role for OT-induced MEF2A activity as major regulator of cellular morphology as well as neuronal connectivity and mitochondrial functioning, with broad implications for a potential treatment of disorders based on morphological alterations or mitochondrial dysfunction.

scholarly journals Myocyte Enhancer Factor 2A (MEF2A) Defines Oxytocin-Induced Morphological Effects and Regulates Mitochondrial Function in Neurons

2020 ◽  
Author(s):  
Magdalena Meyer ◽  
Kerstin Kuffner ◽  
Julia Winter ◽  
Inga D. Neumann ◽  
Christian H. Wetzel ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Cellular Response ◽  
Autism Spectrum ◽  
Neuronal Morphology ◽  
Cellular Respiration ◽  
Morphological Alterations ◽  
Neurite Retraction ◽  
Upstream Regulator ◽  
The Common ◽  
Enhancer Factor

The neuropeptide oxytocin (OT) is a well-described modulator of socio-emotional traits, such as anxiety, stress, social behavior, and pair-bonding, however, when dysregulated, it is associated with adverse psychiatric traits, like various aspects of autism spectrum disorder (ASD). In this study, we identify the transcription factor MEF2A as the common link between OT and cellular changes symptomatic for ASD, encompassing neuronal morphology, connectivity, and mitochondrial function. We provide evidence for MEF2A as the decisive factor defining the cellular response to OT: while OT induces neurite retraction in MEF2A expressing neurons, OT causes neurite outgrowth in absence of MEF2A. A CRISPR-Cas-mediated knockout of MEF2A and retransfection of an active version or permanently inactive mutant, respectively, validated our findings. We also identified the phosphatase calcineurin as the main upstream regulator of OT-induced MEF2A signaling. Further, MEF2A signaling dampens mitochondrial functioning in neurons, as MEF2A knockout cells show increased maximal cellular respiration, spare-respiratory capacity, and total cellular ATP. In summary, we reveal a central role for OT-induced MEF2A as major regulator of cellular morphology as well as neuronal connectivity and mitochondrial functioning, with broad implications for a potential treatment of disorders based on morphological alterations or mitochondrial dysfunction.

scholarly journals Involvement of myocyte enhancer factor 2c in the pathogenesis of autism spectrum disorder

Heliyon ◽  
2021 ◽  
Vol 7 (4) ◽  
pp. e06854
Author(s):  
Rishabh Chaudhary ◽  
Vipul Agarwal ◽  
Arjun Singh Kaushik ◽  
Mujeeba Rehman
Keyword(s):  
Autism Spectrum Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Myocyte Enhancer Factor ◽  
Enhancer Factor

Regulation of hepatic stellate cell activation and growth by transcription factor myocyte enhancer factor 2

2004 ◽  
Vol 127 (4) ◽  
pp. 1174-1188 ◽  
Author(s):  
Xuemin Wang ◽  
Xiaoli Tang ◽  
Xiaoming Gong ◽  
Efsevia Albanis ◽  
Scott L. Friedman ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Hepatic Stellate Cell ◽  
Cell Activation ◽  
Stellate Cell ◽  
Myocyte Enhancer Factor 2 ◽  
Hepatic Stellate Cell Activation ◽  
Myocyte Enhancer Factor ◽  
Enhancer Factor

scholarly journals Angiopoietin-1 Induces Krüppel-like Factor 2 Expression through a Phosphoinositide 3-Kinase/AKT-dependent Activation of Myocyte Enhancer Factor 2

2008 ◽  
Vol 284 (9) ◽  
pp. 5592-5601 ◽  
Author(s):  
Keisuke Sako ◽  
Shigetomo Fukuhara ◽  
Takashi Minami ◽  
Takao Hamakubo ◽  
Haihua Song ◽  
...  
Keyword(s):  
Myocyte Enhancer Factor 2 ◽  
Myocyte Enhancer Factor ◽  
Phosphoinositide 3 Kinase ◽  
Angiopoietin 1 ◽  
Enhancer Factor

scholarly journals Myocyte Enhancer Factor 2C and Nkx2–5 Up-regulate Each Other’s Expression and Initiate Cardiomyogenesis in P19 Cells

1998 ◽  
Vol 273 (52) ◽  
pp. 34904-34910 ◽  
Author(s):  
Ilona S. Skerjanc ◽  
Helen Petropoulos ◽  
Alan G. Ridgeway ◽  
Sharon Wilton
Keyword(s):  
P19 Cells ◽  
Myocyte Enhancer Factor ◽  
Enhancer Factor

scholarly journals Myocyte enhancer factor 2C in hematopoiesis and leukemia

Oncogene ◽  
2013 ◽  
Vol 33 (4) ◽  
pp. 403-410 ◽  
Author(s):  
K Canté-Barrett ◽  
R Pieters ◽  
J P P Meijerink
Keyword(s):  
Myocyte Enhancer Factor ◽  
Enhancer Factor

scholarly journals DNA Methylation of PGC-1α Is Associated With Elevated mtDNA Copy Number and Altered Urinary Metabolites in Autism Spectrum Disorder

2021 ◽  
Vol 9 ◽  
Author(s):  
Sophia Bam ◽  
Erin Buchanan ◽  
Caitlyn Mahony ◽  
Colleen O’Ryan
Keyword(s):  
Autism Spectrum Disorder ◽  
Dna Methylation ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Copy Number ◽  
Autism Spectrum ◽  
Differential Methylation ◽  
Mtdna Copy Number ◽  
Key Genes

Autism spectrum disorder (ASD) is a complex disorder that is underpinned by numerous dysregulated biological pathways, including pathways that affect mitochondrial function. Epigenetic mechanisms contribute to this dysregulation and DNA methylation is an important factor in the etiology of ASD. We measured DNA methylation of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α), as well as five genes involved in regulating mitochondrial homeostasis to examine mitochondrial dysfunction in an ASD cohort of South African children. Using targeted Next Generation bisulfite sequencing, we found differential methylation (p < 0.05) at six key genes converging on mitochondrial biogenesis, fission and fusion in ASD, namely PGC-1α, STOML2, MFN2, FIS1, OPA1, and GABPA. PGC-1α, the transcriptional regulator of biogenesis, was significantly hypermethylated at eight CpG sites in the gene promoter, one of which contained a putative binding site for CAMP response binding element 1 (CREB1) (p = 1 × 10–6). Mitochondrial DNA (mtDNA) copy number, a marker of mitochondrial function, was elevated (p = 0.002) in ASD compared to controls and correlated significantly with DNA methylation at the PGC-1α promoter and there was a positive correlation between methylation at PGC-1α CpG#1 and mtDNA copy number (Spearman’s r = 0.2, n = 49, p = 0.04) in ASD. Furthermore, DNA methylation at PGC-1α CpG#1 and mtDNA copy number correlated significantly (p < 0.05) with levels of urinary organic acids associated with mitochondrial dysfunction, oxidative stress, and neuroendocrinology. Our data show differential methylation in ASD at six key genes converging on PGC-1α-dependent regulation of mitochondrial biogenesis and function. We demonstrate that methylation at the PGC-1α promoter is associated with elevated mtDNA copy number and metabolomic evidence of mitochondrial dysfunction in ASD. This highlights an unexplored role for DNA methylation in regulating specific pathways involved in mitochondrial biogenesis, fission and fusion contributing to mitochondrial dysfunction in ASD.

scholarly journals A myocyte enhancer factor 2D (MEF2D) kinase activated during neuronal apoptosis is a novel target inhibited by lithium

2003 ◽  
Vol 86 (4) ◽  
pp. 1055-1055
Author(s):  
Daniel A. Linseman ◽  
Brandon J. Cornejo ◽  
Shoshona S. Le ◽  
Mary Kay Meintzer ◽  
Tracey A. Laessig ◽  
...  
Keyword(s):  
Neuronal Apoptosis ◽  
Myocyte Enhancer Factor ◽  
Novel Target ◽  
Enhancer Factor

scholarly journals Nemo-Like Kinase-Myocyte Enhancer Factor 2A Signaling Regulates Anterior Formation in Xenopus Development

2007 ◽  
Vol 27 (21) ◽  
pp. 7623-7630 ◽  
Author(s):  
Kiyotoshi Satoh ◽  
Junji Ohnishi ◽  
Atsushi Sato ◽  
Michio Takeyama ◽  
Shun-ichiro Iemura ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Neural Development ◽  
Marker Genes ◽  
Neural Structure ◽  
Animal Pole ◽  
Endogenous Expression ◽  
Myocyte Enhancer Factor ◽  
Molecular Events ◽  
Bone Morphogenic Protein 4 ◽  
Enhancer Factor

ABSTRACT The development of anterior neural structure in Xenopus laevis requires the inhibition of bone morphogenic protein 4 and Wnt signaling. We previously reported that Nemo-like kinase (NLK) negatively regulates Wnt signaling via the phosphorylation of T-cell factor/lymphoid enhancer factor. However, the molecular events occurring downstream of NLK pathways in early neural development remain unclear. In the present study, we identified the transcription factor myocyte enhancer factor 2A (MEF2A) as a novel substrate for NLK. NLK regulates the function of Xenopus MEF2A (xMEF2A) via phosphorylation, and this modification can be inhibited by the depletion of endogenous NLK. In Xenopus embryos, the depletion of either NLK or MEF2A results in a severe defect in anterior development. The endogenous expression of anterior markers was blocked by the depletion of endogenous Xenopus NLK (xNLK) or xMEF2A but, notably, not by the depletion of other xMEF2 family proteins, xMEF2C and xMEF2D. Defects in head formation or the expression of the anterior marker genes caused by the depletion of endogenous xMEF2A could be eliminated by the expression of wild-type xMEF2A, but not xMEF2A containing mutated xNLK phosphorylation sites. Furthermore, the expression of xNLK-induced anterior markers was efficiently blocked by the depletion of endogenous xMEF2A in animal pole explants. These results show that NLK specifically regulates the MEF2A activity required for anterior formation in Xenopus development.

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