Leptin stimulates synaptogenesis in hippocampal neurons via KLF4 and SOCS3 inhibition of STAT3 signaling
Autor: | Mingyan Zhu, Gary A. Wayman, Soren Impey, Crystal Dillon, Talley J. Lambert, Gulcan Semra Sahin, Suzanne M. Appleyard, Hiroko Shiina, Matasha Dhar, Bradley D. Winters |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Leptin Male STAT3 Transcription Factor Dendritic spine Dendritic Spines Neurogenesis Synaptogenesis Kruppel-Like Transcription Factors Hippocampus Biology Hippocampal formation Article Rats Sprague-Dawley 03 medical and health sciences Cellular and Molecular Neuroscience Glutamatergic Kruppel-Like Factor 4 0302 clinical medicine Animals SOCS3 Molecular Biology Neurons digestive oral and skin physiology Cell Biology Cell biology Rats 030104 developmental biology Suppressor of Cytokine Signaling 3 Protein Synapses biology.protein Female Transcriptome 030217 neurology & neurosurgery hormones hormone substitutes and hormone antagonists Neurotrophin Signal Transduction |
Zdroj: | Mol Cell Neurosci |
ISSN: | 1095-9327 |
Popis: | Normal development of neuronal connections in the hippocampus requires neurotrophic signals, including the cytokine leptin. During neonatal development, leptin induces formation and maturation of dendritic spines, the main sites of glutamatergic synapses in the hippocampal neurons. However, the molecular mechanisms for leptin-induced synaptogenesis are not entirely understood. In this study, we reveal two novel targets of leptin in developing hippocampal neurons and address their role in synaptogenesis. First target is Kruppel-Like Factor 4 (KLF4), which we identified using a genome-wide target analysis strategy. We show that leptin upregulates KLF4 in hippocampal neurons and that leptin signaling is important for KLF4 expression in vivo. Furthermore, KLF4 is required for leptin-induced synaptogenesis, as shKLF4 blocks and upregulation of KLF4 phenocopies it. We go on to show that KLF4 requires its signal transducer and activator of transcription 3 (STAT3) binding site and thus potentially blocks STAT3 activity to induce synaptogenesis. Second, we show that leptin increases the expression of suppressor of cytokine signaling 3 (SOCS3), another well-known inhibitor of STAT3, in developing hippocampal neurons. SOCS3 is also required for leptin-induced synaptogenesis and sufficient to stimulate it alone. Finally, we show that constitutively active STAT3 blocks the effects of leptin on spine formation, while the targeted knockdown of STAT3 is sufficient to induce it. Overall, our data demonstrate that leptin increases the expression of both KLF4 and SOCS3, inhibiting the activity of STAT3 in the hippocampal neurons and resulting in the enhancement of glutamatergic synaptogenesis during neonatal development. |
Databáze: | OpenAIRE |
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