A vital role of tubulin-tyrosine-ligase for neuronal organization

Proc Natl Acad Sci U S A. 2005 May 31;102(22):7853-8. doi: 10.1073/pnas.0409626102. Epub 2005 May 17.

Abstract

Tubulin is subject to a special cycle of detyrosination/tyrosination in which the C-terminal tyrosine of alpha-tubulin is cyclically removed by a carboxypeptidase and readded by a tubulin-tyrosine-ligase (TTL). This tyrosination cycle is conserved in evolution, yet its physiological importance is unknown. Here, we find that TTL suppression in mice causes perinatal death. A minor pool of tyrosinated (Tyr-)tubulin persists in TTL null tissues, being present mainly in dividing TTL null cells where it originates from tubulin synthesis, but it is lacking in postmitotic TTL null cells such as neurons, which is apparently deleterious because early death in TTL null mice is, at least in part, accounted for by a disorganization of neuronal networks, including a disruption of the cortico-thalamic loop. Correlatively, cultured TTL null neurons display morphogenetic anomalies including an accelerated and erratic time course of neurite outgrowth and a premature axonal differentiation. These anomalies may involve a mislocalization of CLIP170, which we find lacking in neurite extensions and growth cones of TTL null neurons. Our results demonstrate a vital role of TTL for neuronal organization and suggest a requirement of Tyr-tubulin for proper control of neurite extensions.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Blotting, Western
  • Brain / anatomy & histology
  • Carbocyanines
  • Cell Differentiation / physiology
  • Cells, Cultured
  • Histological Techniques
  • Mice
  • Mice, Knockout
  • Microscopy, Fluorescence
  • Microscopy, Video
  • Microtubule-Associated Proteins / metabolism
  • Neoplasm Proteins / metabolism
  • Nerve Net / anatomy & histology
  • Neurites / metabolism*
  • Neurons / cytology
  • Neurons / metabolism*
  • Peptide Synthases / genetics
  • Peptide Synthases / metabolism*
  • RNA, Small Interfering / genetics
  • Tubulin / metabolism*

Substances

  • Carbocyanines
  • Microtubule-Associated Proteins
  • Neoplasm Proteins
  • RNA, Small Interfering
  • Tubulin
  • cytoplasmic linker protein 170
  • carbocyanine dye DiIC12(3)
  • Peptide Synthases
  • tyrosyltubulin ligase