Neuronal-Specific TUBB3 Is Not Required for Normal Neuronal Function but Is Essential for Timely Axon Regeneration
Alban Latremoliere,
Long Cheng,
Michelle DeLisle,
Chen Wu,
Sheena Chew,
Elizabeth B. Hutchinson,
Andrew Sheridan,
Chloe Alexandre,
Frederic Latremoliere,
Shu-Hsien Sheu,
Sara Golidy,
Takao Omura,
Eric A. Huebner,
Yanjie Fan,
Mary C. Whitman,
Elaine Nguyen,
Crystal Hermawan,
Carlo Pierpaoli,
Max A. Tischfield,
Clifford J. Woolf,
Elizabeth C. Engle
Affiliations
Alban Latremoliere
Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, USA; Department of Neurobiology, Harvard Medical School, Boston, MA, USA
Long Cheng
Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, USA; Department of Neurology, Boston Children’s Hospital, Boston, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA
Michelle DeLisle
Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, USA; Department of Neurology, Boston Children’s Hospital, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA
Chen Wu
Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, USA; Department of Neurology, Boston Children’s Hospital, Boston, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA
Sheena Chew
Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, USA; Department of Neurology, Boston Children’s Hospital, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA
Elizabeth B. Hutchinson
Quantitative Medical Imaging Section, National Institute of Biomedical Imaging and Bioengineering, NIH, Bethesda, MD, USA; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA
Andrew Sheridan
Department of Neurology, Boston Children’s Hospital, Boston, MA, USA
Chloe Alexandre
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Frederic Latremoliere
Department of Mathematics, University of Denver, Denver, CO, USA
Shu-Hsien Sheu
Department of Pathology and Department of Cardiology, Boston Children’s Hospital, Boston, MA, USA
Sara Golidy
Department of Neurology, Boston Children’s Hospital, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA
Takao Omura
Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, USA; Department of Neurobiology, Harvard Medical School, Boston, MA, USA; Department of Orthopedic Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan
Eric A. Huebner
Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, USA; Department of Neurobiology, Harvard Medical School, Boston, MA, USA
Yanjie Fan
Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, USA; Department of Neurology, Boston Children’s Hospital, Boston, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA
Mary C. Whitman
Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, USA; Department of Ophthalmology, Boston Children’s Hospital, Boston, MA, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
Elaine Nguyen
Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, USA; Department of Ophthalmology, Boston Children’s Hospital, Boston, MA, USA
Crystal Hermawan
Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, USA; Department of Neurology, Boston Children’s Hospital, Boston, MA, USA
Carlo Pierpaoli
Quantitative Medical Imaging Section, National Institute of Biomedical Imaging and Bioengineering, NIH, Bethesda, MD, USA; The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA
Max A. Tischfield
Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, USA; Department of Neurology, Boston Children’s Hospital, Boston, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA
Clifford J. Woolf
Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, USA; Department of Neurobiology, Harvard Medical School, Boston, MA, USA
Elizabeth C. Engle
Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, USA; Department of Neurology, Boston Children’s Hospital, Boston, MA, USA; Department of Ophthalmology, Boston Children’s Hospital, Boston, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA; Corresponding author
Summary: We generated a knockout mouse for the neuronal-specific 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 β-tubulin levels in Tubb3−/− 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. : 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. Keywords: tubulin, TUBB3, development, mouse, axonal growth, microtubule dynamics, sensory recovery, spot culture, post-translational modifications, diffusion tensor imaging
