The mechanisms that coordinate and balance a complex network of opposing regulators to control Schwann cell (SC) differentiation remain elusive. Here we demonstrate that zinc-finger E-box binding-homeobox 2 (Zeb2/Sip1) transcription factor is a critical intrinsic timer that controls the onset of Schwann cell (SC) differentiation by recruiting HDAC1/2-NuRD co-repressor complexes. Zeb2 deletion arrests SCs at an undifferentiated state during peripheral nerve development and inhibits remyelination after injury. Zeb2 antagonizes inhibitory effectors including Notch and Sox2. Importantly, genome-wide transcriptome analysis reveals a Zeb2 target gene, encoding the Notch effector Hey2, as a potent inhibitor for SC differentiation. Strikingly, a genetic Zeb2 variant, which is associated with Mowat-Wilson syndrome, disrupts the interaction with HDAC1/2-NuRD and abolishes Zeb2 activity for SC differentiation. Therefore, Zeb2 controls SC maturation by recruiting HDAC1/2-NuRD complexes and inhibiting a novel Notch-Hey2 signaling axis, pointing to the critical role of HDAC1/2-NuRD activity in peripheral neuropathies caused by ZEB2 mutations.

Cutaneous inflammation alters the function of primary afferents and gene expression in the affected dorsal root ganglia (DRGs). However specific mechanisms of injury-induced peripheral afferent sensitization and behavioral hypersensitivity during development are not fully understood. Recent studies in children suggest a potential role for growth hormone (GH) in pain modulation. GH modulates homeostasis and tissue repair after injury, but how GH effects nociception in neonates is not known. To determine if GH played a role in modulating sensory neuron function and hyper-responsiveness during skin inflammation in young mice, we examined behavioral hypersensitivity and the response properties of cutaneous afferents using an ex vivo hairy skin-saphenous nerve-dorsal root ganglion (DRG)-spinal cord preparation. Results show that inflammation of the hairy hindpaw skin initiated at either postnatal day 7 (P7) or P14 reduced GH levels specifically in the affected skin. Furthermore, pretreatment of inflamed mice with exogenous GH reversed mechanical and thermal hypersensitivity in addition to altering nociceptor function. These effects may be mediated via an upregulation of insulin-like growth factor 1 receptor (IGFr1) as GH modulated the transcriptional output of IGFr1 in DRG neurons in vitro and in vivo. Afferent-selective knockdown of IGFr1 during inflammation also prevented the observed injury-induced alterations in cutaneous afferents and behavioral hypersensitivity similar to that following GH pretreatment. These results suggest that GH can block inflammation-induced nociceptor sensitization during postnatal development leading to reduced pain-like behaviors, possibly by suppressing the upregulation of IGFr1 within DRGs.

Research in the Kim laboratory is supported by the Celgene Corporation, Doris Duke Charitable Foundation, LEO Pharma, and National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (K08AR065577, R01AR070116, R01AR077007, and R21AI167047) (to B.S.K.). A.M.T. and M.R.M. are supported by National Institute of Allergy and Infectious Diseases (NIAID) (T32AI007163). A.M.T. and L.K.O. are supported by National Heart, Lung, and Blood Institute (NHLBI) (T32HL007317). A.M.T. is supported by NIAID (F30AI154912). Research in the Gereau laboratory involving human dorsal root ganglia research is supported by National Institute of Neurological Disorders and Strokes (NINDS) (R01NS042595) (to R.W.G.). Research in the Alexander-Brett laboratory is supported by NHLBI (R01HL152245) and the Burroughs Welcome Fund (1014685) (to J.A.B). Research in the Cavalli laboratory is supported by the McDonnell Center for Cellular and Molecular Neurobiology and NINDS (R01NS111719) (to V.C.). O.A. is supported by the postdoctoral fellowship from the McDonnell Center for Cellular and Molecular Neurobiology. Research in the Davidson laboratory is supported by NINDS (RF1NS113881) (to S.D.). Research in the Hu laboratory is supported by National Institute for Alcohol Abuse and Alcoholism (NIAAA) (R01AA027065), NIAMS (R01AR077183), and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01DK103901) (to H.H.

Rationale: Psoriasis is a chronic inflammatory disease caused by a complex interplay between the immune and nervous systems with recurrent scaly skin plaques, thickened stratum corneum, infiltration and activation of inflammatory cells, and itch. Despite an increasing availability of immune therapies, they often have adverse effects, high costs, and dissociated effects on inflammation and itch. Activation of sensory neurons innervating the skin and TRPV1 (transient receptor potential vanilloid 1) are emerging as critical components in the pathogenesis of psoriasis, but little is known about their endogenous inhibitors. Recent studies have demonstrated that resolvins, endogenous lipid mediators derived from omega-3 fatty acids, are potent inhibitors of TRP channels and may offer new therapies for psoriasis without known adverse effects. Methods: We used behavioral, electrophysiological and biochemical approaches to investigate the therapeutic effects of resolvin D3 (RvD3), a novel family member of resolvins, in a preclinical model of psoriasis consisting of repeated topical applications of imiquimod (IMQ) to murine skin, which provokes inflammatory lesions that resemble human psoriasis. Results: We report that RvD3 specifically reduced TRPV1-dependent acute pain and itch in mice. Mechanistically, RvD3 inhibited capsaicin-induced TRPV1 currents in dissociated dorsal root ganglion (DRG) neurons via the N-formyl peptide receptor 2 (i.e. ALX/FPR2), a G-protein coupled receptor. Single systemic administration of RvD3 (2.8 mg/kg) reversed itch after IMQ, and repeated administration largely prevented the development of both psoriasiform itch and skin inflammation with concomitant decreased in calcitonin gene-related peptide (CGRP) expression in DRG neurons. Accordingly, specific knockdown of CGRP in DRG was sufficient to prevent both psoriasiform itch and skin inflammation similar to the effects following RvD3 administration. Finally, we elevated the translational potential of this study by showing that RvD3 significantly inhibited capsaicin-induced TRPV1 activity and CGRP release in human DRG neurons. Conclusions: Our findings demonstrate a novel role for RvD3 in regulating TRPV1/CGRP in mouse and human DRG neurons and identify RvD3 and its neuronal pathways as novel therapeutic targets to treat psoriasis.