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Oxytocin alters the morphology of hypothalamic neurons via the transcription factor myocyte enhancer factor 2A
Magdalena Meyer1, Ilona Berger2, Julia Winter1
1Department of Behavioral and Molecular Neurobiology, University of Regensburg, Regensburg, Germany.
Abstract:
Oxytocin (OT) has gained attention not only as anxiolytic drug and as potential treatment option for autistic children; it also acts as a growth and differentiation factor in neuronal cells. While behavioral effects of OT have been studied in detail, knowledge about the cellular effects of OT is relatively sparse. In this study, we present evidence for three hypotheses: 1) OT leads to neurite retraction in hypothalamic neurons via the OT receptor (OTR) 2) The transcription factor MEF-2A is a central regulator of OT-induced neurite retraction, and 3) The MAPK pathway is critical for OT-induced MEF-2A activation. Incubation of rat hypothalamic H32 cells with 10 nM to 1 μM OT, vasopressin, and the specific OTR agonist TGOT, over the course of 12 h resulted in a time-dependent, significant retraction of neurites. In addition, the size of the nuclear compartment increased, whereas the overall cell size remained unchanged. OT treatment for 10 h increased the cellular viability significantly, and this effect could be blocked by a specific OTR antagonist, providing evidence for a specific and pro-active effect of OT on neurite retraction, and not as an unspecific side effect of apoptosis. The molecular mechanism that controls OT-induced neurite retraction includes a reduced phosphorylation of the transcription factor MEF-2A at Serine 408 (S408). This dephosphorylation is under the control of the OTR-coupled MAPK pathway, as blocking MEK1/2 by U0126 inhibited MEF-2A activation and subsequent neurite retraction. The siRNA-mediated knockdown of MEF-2A prevented the OT-induced neurite retraction, providing direct evidence for a role of MEF-2A in morphological alterations induced by OT treatment. In summary, the present study reveals a previously unknown OTR-coupled MAPK-MEF-2A pathway, which is responsible for OT-induced neurite retraction of hypothalamic neurons.
Insights
Oxytocin (OT) causes hypothalamic neurons to retract their neurites through the oxytocin receptor (OTR) and MAPK pathway, involving transcription factor MEF-2A. This reveals a novel OTR-coupled pathway regulating neuronal morphology.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Oxytocin (OT) is known for behavioral effects and potential autism treatments, but its cellular roles in neurons are less understood.
- Neurite morphology is crucial for neuronal function and development, yet the specific molecular mechanisms regulating OT-induced changes remain largely unelucidated.
Purpose of the Study:
- To investigate the cellular effects of oxytocin (OT) on hypothalamic neurons, specifically focusing on neurite morphology.
- To elucidate the molecular pathways, including the oxytocin receptor (OTR), transcription factor MEF-2A, and MAPK pathway, involved in OT-induced neurite retraction.
Main Methods:
- Rat hypothalamic H32 cells were treated with OT, vasopressin, and an OTR agonist.
- Neurite retraction was quantified, and nuclear size was measured.
- Cellular viability assays were performed, and molecular mechanisms were explored using MEK1/2 inhibitors (U0126) and siRNA-mediated knockdown of MEF-2A.
Main Results:
- Oxytocin treatment induced significant, time-dependent neurite retraction and increased nuclear size in hypothalamic neurons.
- OT treatment enhanced cellular viability, indicating a specific, non-apoptotic effect.
- The OTR-coupled MAPK pathway was critical, mediating the dephosphorylation of MEF-2A at Serine 408, which was essential for OT-induced neurite retraction.
Conclusions:
- Oxytocin, acting via its receptor (OTR), triggers neurite retraction in hypothalamic neurons through a novel MAPK-MEF-2A signaling pathway.
- MEF-2A acts as a key regulator in OT-induced morphological alterations of neurons.
- This study uncovers a new molecular mechanism by which oxytocin influences neuronal structure and function.
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