The LMTK1-TBC1D9B-Rab11A cascade regulates dendritic spine formation via endosome trafficking

Hironori Nishino, Taro Saito, Ran Wei, Tetsuya Takano, Koji Tsutsumi, Makoto Taniguchi, Kanae Ando, Mineko Tomomura, Mitsunori Fukuda, Shin Ichi Hisanaga

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)


Dendritic spines are postsynaptic protrusions at excitatory synapses that are critical for proper neuronal synaptic transmission. While lipid and protein membrane components are necessary for spine formation, it is largely unknown how they are recruited to developing spines. Endosomal trafficking is one mechanism that may influence this development. We recently reported that Lemur kinase 1A (LMTK1A), a membrane-bound Ser/Thr kinase, regulates trafficking of endosomes in neurons. LMTK1 has been shown to be a p35 Cdk5 activator-binding protein and a substrate for Cdk5-p35; however, its neuronal function has not been sufficiently studied. Here, we investigate the role of LMTK1 in spine formation. Depletion of LMTK1 increases spine formation, maturation, and density in primary cultured neurons and in mouse brain of either sex. Additionally, expression of kinase-negative LMTK1 stimulates spine formation in primary neurons and in vivo. LMTK1 controls spineformationthrough Rab11, a regulator of recycling endosometrafficking. We identify TBC1D9B, a Rab11A GTPase-activating protein (Rab11A GAP), as a LMTK1 binding protein, and find that TBC1D9B mediates LMTK1 activity on Rab11A. TBC1D9B inactivates Rab11A under the control of LMTK1A. Further, by analyzing the effect of decreased TBC1D9B expression in primary neurons, we demonstrate that TBC1D9B indeed regulates spine formation. This is the first demonstration of the biological function of TBC1D9B. Together, with the regulation of LMTK1 by Cdk5-p35, we propose the Cdk5-LMTK1-TBC1D9B-Rab11A cascade as a novel signaling mechanism regulating endosomal transport for synapse formation and function.

Original languageEnglish
Pages (from-to)9491-9502
Number of pages12
JournalJournal of Neuroscience
Issue number48
Publication statusPublished - 2019 Nov 27


  • Cdk5
  • Endosome
  • Gap
  • Membrane Trafficking
  • Rab
  • Spine


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