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      Neuronal-Specific TUBB3 Is Not Required for Normal Neuronal Function but Is Essential for Timely Axon Regeneration

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          SUMMARY

          We generated a knockout mouse for the neuronalspecific β-tubulin isoform Tubb3 to investigate its role in nervous system formation and maintenance. Tubb3 −/− mice have no detectable neurobehavioral or neuropathological deficits, and upregulation of mRNA and protein of the remaining β-tubulin isotypes results in equivalent total b-tubulin levels in Tubb 3 −/− and wild-type mice. Despite similar levels of total β-tubulin, adult dorsal root ganglia lacking TUBB3 have decreased growth cone microtubule dynamics and a decreased neurite outgrowth rate of 22% in vitro and in vivo. The effect of the 22% slower growth rate is exacerbated for sensory recovery, where fibers must reinnervate the full volume of the skin to recover touch function. Overall, these data reveal that, while TUBB3 is not required for formation of the nervous system, it has a specific role in the rate of peripheral axon regeneration that cannot be replaced by other β-tubulins.

          In Brief

          Latremoliere et al. show that the neuronal-specific tubulin isoform TUBB3 is not required for normal development and function of the nervous system. Lack of TUBB3 decreases the dynamics of microtubules in growth cones, and this reduces axonal growth after peripheral nerve injury and strongly delays functional recovery.

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          Most cited references41

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          Sustained axon regeneration induced by co-deletion of PTEN and SOCS3

          A formidable challenge in neural repair in the adult central nervous system (CNS) is the long distances that regenerating axons often need to travel in order to reconnect with their targets. Thus, a sustained capacity for axon regeneration is critical for achieving functional restoration. Although deletion of either Phosphatase and tensin homolog (PTEN), a negative regulator of mammalian target of rapamycin (mTOR), or suppressor of cytokine signaling 3 (SOCS3), a negative regulator of Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, in adult retinal ganglion cells (RGCs) individually promoted significant optic nerve regeneration, such regrowth tapered off around two weeks after the crush injury 1,2 . Remarkably, we now find that simultaneous deletion of both PTEN and SOCS3 enables robust and sustained axon regeneration. We further show that PTEN and SOCS3 regulate two independent pathways that act synergistically to promote enhanced axon regeneration. Gene expression analyses suggest that double deletion not only results in the induction of many growth-related genes, but also allows RGCs to maintain the expression of a repertoire of genes at the physiological level after injury. Our results reveal concurrent activation of mTOR and STAT3 pathways as a key for sustaining long-distance axon regeneration in adult CNS, a crucial step toward functional recovery.
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            Microtubule stabilization reduces scarring and causes axon regeneration after spinal cord injury.

            Hypertrophic scarring and poor intrinsic axon growth capacity constitute major obstacles for spinal cord repair. These processes are tightly regulated by microtubule dynamics. Here, moderate microtubule stabilization decreased scar formation after spinal cord injury in rodents through various cellular mechanisms, including dampening of transforming growth factor-β signaling. It prevented accumulation of chondroitin sulfate proteoglycans and rendered the lesion site permissive for axon regeneration of growth-competent sensory neurons. Microtubule stabilization also promoted growth of central nervous system axons of the Raphe-spinal tract and led to functional improvement. Thus, microtubule stabilization reduces fibrotic scarring and enhances the capacity of axons to grow.
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              Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance.

              We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific beta-tubulin isotype III, result in a spectrum of human nervous system disorders that we now call the TUBB3 syndromes. Each mutation causes the ocular motility disorder CFEOM3, whereas some also result in intellectual and behavioral impairments, facial paralysis, and/or later-onset axonal sensorimotor polyneuropathy. Neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerves and dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. A knock-in disease mouse model reveals axon guidance defects without evidence of cortical cell migration abnormalities. We show that the disease-associated mutations can impair tubulin heterodimer formation in vitro, although folded mutant heterodimers can still polymerize into microtubules. Modeling each mutation in yeast tubulin demonstrates that all alter dynamic instability whereas a subset disrupts the interaction of microtubules with kinesin motors. These findings demonstrate that normal TUBB3 is required for axon guidance and maintenance in mammals.
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                Author and article information

                Journal
                101573691
                39703
                Cell Rep
                Cell Rep
                Cell reports
                2211-1247
                27 August 2018
                14 August 2018
                25 September 2018
                : 24
                : 7
                : 1865-1879.e9
                Affiliations
                [1 ]Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, USA
                [2 ]Department of Neurology, Boston Children’s Hospital, Boston, MA, USA
                [3 ]Department of Ophthalmology, Boston Children’s Hospital, Boston, MA, USA
                [4 ]Department of Neurobiology, Harvard Medical School, Boston, MA, USA
                [5 ]Department of Neurology, Harvard Medical School, Boston, MA, USA
                [6 ]Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
                [7 ]Howard Hughes Medical Institute, Chevy Chase, MD, USA
                [8 ]Quantitative Medical Imaging Section, National Institute of Biomedical Imaging and Bioengineering, NIH, Bethesda, MD, USA
                [9 ]The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA
                [10 ]Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
                [11 ]Department of Mathematics, University of Denver, Denver, CO, USA
                [12 ]Department of Pathology and Department of Cardiology, Boston Children’s Hospital, Boston, MA, USA
                [13 ]Department of Orthopedic Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan
                [16 ]Present address: Neurosurgery Department, Johns Hopkins School of Medicine, Baltimore, MD, USA
                [17 ]Present address: Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
                [18 ]Present address: Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA
                [19 ]Present address: Janelia Research Campus, HHMI, Ashburn, VA, USA
                [20 ]Present address: Shanghai Institute for Pediatric Research, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
                [21 ]Present address: Cell Biology and Neuroscience, Rutgers University, Piscataway Township, NJ, USA
                [22 ]Lead Contact
                Author notes

                AUTHOR CONTRIBUTIONS

                Conceptualization and methodology, A.L., L.C., and E.C.E.; Investigation, A.L. and L.C. with assistance from M.D., C.W., S.C., E.B.H., A.S., C.A., F.L., S.-H.S., S.G., T.O., E.B.H., Y.F., M.C.W., E.N., C.H., C.P., M.A.T., C.J.W., and E.C.E.; Formal analysis, A.L., L.C., M.D., E.B.H., F.L., C.A., and E.A.H.; Writing of original draft, A.L., L.C., C.J.W., and E.C.E.; and Manuscript review & editing, A.L., L.C., C.J.W., E.C.E., with contributions from all authors.

                Article
                NIHMS1504958
                10.1016/j.celrep.2018.07.029
                6155462
                30110642
                479a2c54-c022-4aa5-8b87-9f410972a581

                1865 This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).

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                Cell biology
                Cell biology

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