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Ligand-Induced GPR110 Activation Facilitates Axon Growth After Injury

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Ligand-Induced GPR110 Activation Facilitates Axon Growth After Injury International Journal of Molecular Sciences Article Ligand-Induced GPR110 Activation Facilitates Axon Growth after Injury Heungsun Kwon 1, Karl Kevala 1, Hu Xin 2, Samarjit Patnaik 2, Juan Marugan 2 and Hee-Yong Kim 1,*,† 1 Laboratory of Molecular Signaling, NIAAA, National Institutes of Health, 5625 Fishers Lane Room 3S-02, Rockville, MD 20892, USA; [email protected] (H.K.); [email protected] (K.K.) 2 Division of Pre-Clinical Innovation, NCATS, National Institutes of Health, Rockville, MD 20852, USA; [email protected] (H.X.); [email protected] (S.P.); [email protected] (J.M.) * Correspondence: [email protected]; Tel.: +1-301-402-8746; Fax: +1-301-594-0035 † Laboratory of Molecular Signaling, National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Rm. 3N-07, Bethesda, MD 20892, USA. Abstract: Recovery from axonal injury is extremely difficult, especially for adult neurons. Here, we demonstrate that the activation of G-protein coupled receptor 110 (GPR110, ADGRF1) is a mechanism to stimulate axon growth after injury. N-docosahexaenoylethanolamine (synaptamide), an endogenous ligand of GPR110 that promotes neurite outgrowth and synaptogenesis in developing neurons, and a synthetic GPR110 ligand stimulated neurite growth in axotomized cortical neurons and in retinal explant cultures. Intravitreal injection of GPR110 ligands following optic nerve crush injury promoted axon extension in adult wild-type, but not in gpr110 knockout, mice. In vitro axotomy or in vivo optic nerve injury rapidly induced the neuronal expression of gpr110. Activating the developmental mechanism of neurite outgrowth by specifically targeting GPR110 that is upregulated upon injury may provide a novel strategy for stimulating axon growth after nerve injury in adults. Citation: Kwon, H.; Kevala, K.; Xin, Keywords: GPR110; synaptamide; cAMP/PKA; axon; optic nerve; microfluidic culture platform; H.; Patnaik, S.; Marugan, J.; Kim, H.-Y. Ligand-Induced GPR110 Activation retinal explant culture Facilitates Axon Growth after Injury. Int. J. Mol. Sci. 2021, 22, 3386. https://doi.org/10.3390/ijms 22073386 1. Introduction Despite extensive efforts to develop repair strategies, injured CNS nerves remain Academic Editor: Pavla Jendelova difficult to regenerate in adulthood [1], largely due to inhibited intrinsic axon growth capacity [2], the formation of a myelin-associated growth-inhibitory environment and Received: 5 March 2021 scarring around the lesion site [3], and increased neuronal cell death [4]. However, axon Accepted: 22 March 2021 regeneration has been demonstrated through manipulating genes or signaling pathways to Published: 25 March 2021 stimulate axon growth potential and to promote neuronal survival [5,6]. The induction of cyclic adenosine monophosphate (cAMP) signaling has also emerged as a promising strat- Publisher’s Note: MDPI stays neutral egy for stimulating axon growth and nerve cell migration across inhibitory substrates [7–9]. with regard to jurisdictional claims in Previously, we have demonstrated that N-docosahexaenoylethanolamine (synaptamide), published maps and institutional affil- an endogenous metabolite of docosahexaenoic acid (DHA, 22:6n-3), potently promotes iations. neurite outgrowth and synaptogenesis by binding to the G-protein coupled receptor 110 (GPR110, ADGRF1) and increasing cAMP in developing neurons [10,11]. GPR110 is an ad- hesion GPCR, and its expression in the brain is highest during development but diminishes in adulthood [10,11]. In the present study, we tested whether this endogenous mechanism Copyright: © 2021 by the authors. for developmental neurite outgrowth is applicable to axon growth after injury. We found Licensee MDPI, Basel, Switzerland. that GPR110 activation by an endogenous or synthetic ligand can stimulate axon growth This article is an open access article after injury and after crush-induced optic nerve injury in adult mice. distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Int. J. Mol. Sci. 2021, 22, 3386. https://doi.org/10.3390/ijms22073386 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 17 Int. J. Mol. Sci. 2021, 22, 3386 2. Results 2 of 16 2.1. Axon Growth Is Stimulated by Somal or Axonal Treatment with Synaptamide We have previously demonstrated that synaptamide stimulated neurite growth in 2. Results cortical cultures with an IC50 value in the low nM range [10]. We tested whether synap- 2.1. Axon Growth Is Stimulated by Somal or Axonal Treatment with Synaptamide tamide-induced axon growth is due to somal or axonal stimulation of GPR110 using cor- tical neuronsWe have previouslycultured in demonstrated a microfluidic that culture synaptamide platform, stimulated where neurite two chambers growth in cor-are sepa- ratedtical cultures by 500 withµm of an thin IC50 valuegrooves in the (Figure low nM 1A) range [12]. [10 We]. We observed tested whether stimulated synaptamide- axon growth induced axon growth is due to somal or axonal stimulation of GPR110 using cortical after either somal or axonal application of synaptamide (Figure 1B,C), as expected by the neurons cultured in a microfluidic culture platform, where two chambers are separated gpr110by 500 expressionµm of thin in grooves both soma (Figure and1A) distal [ 12]. axon We observeds (Figure stimulated1D). The presence axon growth of GPR110 af- in theter eitherdistal somalaxons orwas axonal further application indicated of synaptamideby the endocytic (Figure puncta1B,C), asthat expected were visualized by the by bodipy–synaptamide,gpr110 expression in both a fluorescent soma and distal GPR110 axons lig (Figureand [10],1D). and The were presence colocalized of GPR110 with in clath- rinthe (Figure distal axons 1E). was further indicated by the endocytic puncta that were visualized by bodipy–synaptamide, a fluorescent GPR110 ligand [10], and were colocalized with clathrin (Figure1E). Figure 1. Axon growth promoted by either somal or axonal treatment of synaptamide. (A) Schematic representation of a Figuremicrofluidic 1. Axon culture growth platform promoted with by two either chambers somal separated or axonal by treatment 500 µm of of thin synaptamide. grooves that ( wasA) Schematic used to culture representation primary of a microfluidiccortical neurons culture from platform the mouse with brain two at chambers postnatal day separated 0 (P0). ( Bby) β 500-III tubulinµm of thin immunofluorescence grooves that was micrographs used to culture showing primary corticalthat axon neurons outgrowth from the in primarymouse brain cortical at postnatal neurons was day induced 0 (P0). (B by) β the-III application tubulin immunofluorescence of 10 nM synaptamide micrographs to the axonal showing thator axon somal outgrowth compartment in primary on DIV3 cortical and cultured neurons for was an additionalinduced by 4 days.the application (C) Quantitative of 10 nM results synaptamide of the total to length the axonal of or somalaxons compartment entered in the on axonal DIV3 compartment.and cultured for Synaptamide an additional application 4 days. to (C the) Quantitative cell body or results axonal compartmentof the total length resulted of axons enteredin a 2.2- in the or 1.3-fold axonal increasecompartmen in axont. Synaptamide growth, respectively, application compared to the tocell the body vehicle or axonal control. compartment (D) Relative quantificationresulted in a 2.2- or 1.3-foldof gpr110 increaseexpression in axon in growth, soma and respecti axon determinedvely, compared by RT-PCR to the aftervehicle collecting control. samples (D) Relative separately quantification from the somal of gpr110 or ex- pressionaxonal in compartment soma and axon of the determined two-chamber by culture RT-PCR platform. after coll (E) Internalizationecting samples of separately GPR110 visualized from the by somal a fluorescent or axonal ligand compart- mentbodipy–synaptamide. of the two-chamber After culture 30 min platform. stimulation (E) Internalization of DIV 3 cortical of neurons GPR110 with visualized 20 nM bodipy-synaptamide, by a fluorescent ligand internalized bodipy–syn- aptamide.GPR110 wasAfter detected 30 min as stimulation fluorescent of endocytic DIV 3 cortical puncta (green)neuron overlappings with 20 nM with bodipy-synaptamide, an endocytic marker clathrininternalized H (magenta), GPR110 was detectedconfirming as fluorescent the axonal presenceendocytic of puncta GPR110. (green) Asterisks overlapping (*) represent with endocytic an endocytic GPR110 receptormarker puncta.clathrin Data H (magenta), are expressed confirming as themean axonal± s.e.m.presence with ofn =GPR110. 6 for (B )Asterisk and n = 3s for(*) represent (D) per group. endocytic ** p < 0.01,GPR110 *** p receptor< 0.001 by puncta.t-test; Veh, Data Vehicle are expressed (DMSO); Syn,as mean ± s.e.m.synaptamide. with n = 6 Scale for ( bar,B) and 20 µ mn = (B 3), for 1 µ m(D ()E per). group. ** p < 0.01, *** p < 0.001 by t-test; Veh, Vehicle (DMSO); Syn, synap- tamide. Scale bar, 20 µm (B), 1 µm (E). Int. J. Mol. Sci. 2021, 22, 3386 3 of 16 2.2. Synaptamide Stimulates Axon Regeneration In Vitro through GPR110/cAMP/PKA- Dependent Signaling To examine axon regeneration, we first established an in vitro axon injury model using the microfluidic culture platform. Axons from primary cortical neurons seeded in one chamber were grown sufficiently through these grooves into the other chamber before axotomy was performed. Addition
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