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

doi:10.1016/j.celrep.2018.07.029

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

Cell Rep. 2018 Aug 14;24(7):1865-1879.e9. doi: 10.1016/j.celrep.2018.07.029.

Authors

Alban Latremoliere¹, Long Cheng², Michelle DeLisle³, Chen Wu², Sheena Chew³, Elizabeth B Hutchinson⁴, Andrew Sheridan⁵, Chloe Alexandre⁶, Frederic Latremoliere⁷, Shu-Hsien Sheu⁸, Sara Golidy⁹, Takao Omura¹⁰, Eric A Huebner¹, Yanjie Fan², Mary C Whitman¹¹, Elaine Nguyen¹², Crystal Hermawan¹³, Carlo Pierpaoli⁴, Max A Tischfield², Clifford J Woolf¹, Elizabeth C Engle¹⁴

Affiliations

¹ Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA; Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
² 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.
³ 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.
⁴ 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.
⁵ Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
⁶ Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
⁷ Department of Mathematics, University of Denver, Denver, CO, USA.
⁸ Department of Pathology and Department of Cardiology, Boston Children's Hospital, Boston, MA, USA.
⁹ Department of Neurology, Boston Children's Hospital, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
¹⁰ 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.
¹¹ 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.
¹² Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA; Department of Ophthalmology, Boston Children's Hospital, Boston, MA, USA.
¹³ Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA; Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
¹⁴ 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. Electronic address: elizabeth.engle@childrens.harvard.edu.

Abstract

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.

Keywords: TUBB3; axonal growth; development; diffusion tensor imaging; microtubule dynamics; mouse; post-translational modifications; sensory recovery; spot culture; tubulin.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Action Potentials / physiology
Animals
Female
Ganglia, Spinal / injuries
Ganglia, Spinal / metabolism
Gene Expression Regulation
Male
Maze Learning
Mice
Mice, Knockout
Microtubules / metabolism
Microtubules / ultrastructure
Nerve Regeneration / genetics*
Neuronal Outgrowth / genetics*
Neuronal Plasticity / genetics
Protein Isoforms / genetics*
Protein Isoforms / metabolism
Signal Transduction
Tubulin / deficiency
Tubulin / genetics*

Substances

Protein Isoforms
Tubb3 protein, mouse
Tubulin

Abstract

Publication types

MeSH terms

Substances

Grants and funding