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Deciphering the Crucial Role of the Kappa Opioid Receptor in Adult Neurogenesis

Review of “Kappa opioid receptor controls neural stem cell differentiation via a miR‐7a/Pax6 dependent pathway” from STEM CELLS by Stuart P. Atkinson

Previous research from the laboratory of Chi Xu (Zhejiang Chinese Medical University, Hangzhou, China) demonstrated that morphine, an μ‐opioid receptor (OPRM1) agonist, inhibits the neuronal differentiation of mouse neural stem cells (NSCs) via a pathway that includes protein kinase C epsilon, miR‐181a, and Prospero homeobox protein 1 (Prox1) (See the earlier STEM CELLS studies here and here!) [1, 2]. The authors hoped that understanding more regarding the regulatory mechanisms controlling adult neurogenesis might inform on the development of cognitive functions, such as learning and memory, and the onset of psychiatric disorders.

In their more recent STEM CELLS study [3], the authors shifted their focus to explore a potential role for the κ‐opioid receptor (OPRK1) [4, 5] in adult neurogenesis due to the robust expression of functional OPRK1 in human embryonic NSCs and the proliferation and migration of NSCs in response to OPRK1 ligand stimulation [6]. Fascinatingly, Xu et al. now report that OPRK1, also a crucial mediator of depressive‐like behaviors [7], regulates mouse NSC differentiation and adult neurogenesis in the mouse hippocampus by modulating neurogenesis-associated gene expression through the upregulation of a specific miRNA species.

Initial analyses discovered the significantly higher expression of Oprk1 when compared to other major subtypes of opioid receptors (Oprm1 and Oprd1) in primary NSCs and hippocampal NSCs in adult mice. Exposure of NSCs to OPRK1 agonists failed to influence proliferation or apoptosis; however, OPRK1 agonist treatment did hinder adult neurogenesis by partially inhibiting the neuronal differentiation of NSCs without affecting glia‐specific differentiation.

Mechanistically, OPRK1 agonists prompted the downregulated expression of neurogenesis‐related genes in NSCs by first upregulating the expression of the miR‐7a, which directly interacts with the Pax6 mRNA 3′‐untranslated region to inhibit translation. The subsequent decrease of PAX6 levels, an essential regulator of adult neurogenesis, decreased the direct interaction of PAX6 with the promoter regions of Neurog2 and Neurod1, two critical regulators of neuronal differentiation [8], leading to a significant decrease in their expression and the inhibition of neuronal differentiation in the mouse hippocampus.

The following steps for the authors include defining just how OPRK1 agonists regulated miR‐7a transcription and exploring the potential of miR‐7a and PAX6 as potential therapeutic targets for the treatment of depression.

Can the delineation of those regulatory pathways controlling adult neurogenesis reveal how cognitive functions and psychiatric develop? Stay tuned to the Stem Cells Portal to find out!


References

  1. Xu C, Zhang Y, Zheng H, et al., Morphine Modulates Mouse Hippocampal Progenitor Cell Lineages by Upregulating miR-181a Level. STEM CELLS 2014;32:2961-2972.
  2. Xu C, Zheng H, Loh HH, et al., Morphine Promotes Astrocyte-Preferential Differentiation of Mouse Hippocampal Progenitor Cells via PKCε-Dependent ERK Activation and TRBP Phosphorylation. STEM CELLS 2015;33:2762-2772.
  3. Xu C, Fan W, Zhang Y, et al., Kappa opioid receptor controls neural stem cell differentiation via a miR-7a/Pax6 dependent pathway. STEM CELLS 2021;39:600-616.
  4. Schwarzer C, 30 years of dynorphins — New insights on their functions in neuropsychiatric diseases. Pharmacology & Therapeutics 2009;123:353-370.
  5. Bruchas MR and Chavkin C, Kinase cascades and ligand-directed signaling at the kappa opioid receptor. Psychopharmacology 2010;210:137-147.
  6. Sheng WS, Hu S, Herr G, et al., Human neural precursor cells express functional kappa-opioid receptors. J Pharmacol Exp Ther 2007;322:957-63.
  7. Anderson RI and Becker HC, Role of the Dynorphin/Kappa Opioid Receptor System in the Motivational Effects of Ethanol. Alcoholism: Clinical and Experimental Research 2017;41:1402-1418.
  8. Osumi N, Shinohara H, Numayama-Tsuruta K, et al., Concise Review: Pax6 Transcription Factor Contributes to both Embryonic and Adult Neurogenesis as a Multifunctional Regulator. STEM CELLS 2008;26:1663-1672.