title: O-GlcNAc Transferase Is Essential for Sensory Neuron Survival and Maintenance.
abstract: O-GlcNAc transferase (OGT) regulates a wide range of cellular processes through the addition of theO-GlcNAc sugar moiety to thousands of protein substrates. Because nutrient availability affects the activity of OGT, its role has been broadly studied in metabolic tissues. OGT is enriched in the nervous system, but little is known about its importance in basic neuronal processesin vivoHere, we show that OGT is essential for sensory neuron survival and maintenance in mice. Sensory neuron-specific knock-out of OGT results in behavioral hyposensitivity to thermal and mechanical stimuli accompanied by decreased epidermal innervation and cell-body loss in the dorsal root ganglia. These effects are observed early in postnatal development and progress as animals age. Cultured sensory neurons lacking OGT also exhibit decreased axonal outgrowth. The effects on neuronal healthin vivoare not solely due to disruption of developmental processes, because inducing OGT knock-out in the sensory neurons of adult mice results in a similar decrease in nerve fiber endings and cell bodies. Significant nerve-ending loss occurs before a decrease in cell bodies; this phenotype is indicative of axonal dieback that progresses to neuronal death. Our findings demonstrate that OGT is important in regulating axonal maintenance in the periphery and the overall health and survival of sensory neurons.SIGNIFICANCE STATEMENTWe show the importance ofO-GlcNAc transferase (OGT) for sensory neuron health and survivalin vivoThis study is the first to find that loss of OGT results in neuronal cell death. Moreover, it suggests that aberrantO-GlcNAc signaling can contribute to the development of neuropathy. The sensory neurons lie outside of the blood-brain barrier and therefore, compared to central neurons, may have a greater need for mechanisms of metabolic sensing and compensation. Peripheral sensory neurons in particular are subject to degeneration in diabetes. Our findings provide a foundation for understanding the role of OGT under normal physiological conditions in the peripheral nervous system. This knowledge will be important for gaining greater insight into such disease states as diabetic neuropathy.
authors.affiliation: The F.M. Kirby Neurobiology Center, Boston Children's Hospital, and.|Department of Neurobiology, Harvard Medical School, Boston MA 02115.
authors.forename: Cathy
authors.initials: C
authors.lastname: Su
authors.affiliation: The F.M. Kirby Neurobiology Center, Boston Children's Hospital, and thomas.schwarz@childrens.harvard.edu.|Department of Neurobiology, Harvard Medical School, Boston MA 02115.
authors.forename: Thomas L
authors.identifier: 0000-0001-7532-0250
authors.initials: TL
authors.lastname: Schwarz
mesh_terms: D000818:Animals; D001835:Body Weight / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000235:genetics; D005951:Glucose Tolerance Test; D008124:Locomotion / Q000235:genetics; D008297:Male; D001523:Mental Disorders / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053580:Muscle Strength / Q000235:genetics; D017351:N-Acetylglucosaminyltransferases / Q000172:deficiency / Q000378:metabolism*; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism; D009473:Neuronal Plasticity / Q000235:genetics; D011984:Sensory Receptor Cells / Q000502:physiology*; D013697:Thermosensing / Q000235:genetics; D050819:Transcription Factor Brn-3A / Q000235:genetics / Q000378:metabolism
chemical_list: D062559:NAV1.8 Voltage-Gated Sodium Channel; C494189:Pou4f1 protein, mouse; C568318:Scn10a protein, mouse; D050819:Transcription Factor Brn-3A; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase
keywords: O-GlcNAc transferase; O-GlcNAcylation; degeneration; dorsal root ganglion; sensory neuron