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Peer-reviewedCC BY 4.0The Journal of Clinical Investigation

Microtubule-associated protein 1S phosphorylation regulates dynein-driven transport and synaptogenesis in neurons

  • André T. Lopes1
  • Ondine Janiv1
  • Suzanne Claxton1
  • Sila K. Ultanir1
  1. 1Kinases and Brain Development Lab, The Francis Crick Institute, London, United Kingdom.
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Abstract

Cyclin-dependent kinase like 5 (CDKL5) is a serine-threonine kinase enriched in the mammalian brain whose loss of function causes a severe developmental and epileptic encephalopathy named CDKL5 Deficiency Disorder. We previously showed that CDKL5 phosphorylates the microtubule-associated protein MAP1S, but how this regulates microtubule-dependent functions is not well understood. To address this question, we generated MAP1S phosphomutant mice in which the CDKL5 phosphorylation sites S786 and S812 were mutated to alanine (MAP1S S786/812A; MAP1S SA). Using a microtubule cosedimentation assay, we found that dynein binding to microtubules was reduced in MAP1S SA and CDKL5 knockout (KO) brain lysates, and time-lapse imaging showed impaired dynein motility in dendrites from both genotypes. MAP1S SA mice also exhibited reduced AMPA receptor transport, dendritic spine density, and excitatory synapses, accompanied by anxiety-like behavior and motor, social, and memory deficits relevant to CDD. Mechanistically, MAP1S SA and CDKL5 KO neurons showed increased microtubule stability and reduced tubulin tyrosination, consistent with excessive MAP1S-mediated stabilization. Restoring tubulin tyrosination by expressing tubulin-tyrosine ligase rescued dynein transport defects. Together, these findings identify MAP1S phosphorylation as a critical regulator of microtubule dynamics and dynein-dependent transport.

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Cite

BibTeXRIS
BibTeX
@article{lopes2026microtubuleassociated,
  title = {{Microtubule-associated protein 1S phosphorylation regulates dynein-driven transport and synaptogenesis in neurons}},
  author = {André T. Lopes and Ondine Janiv and Suzanne Claxton and Sila K. Ultanir},
  journal = {The Journal of Clinical Investigation},
  year = {2026},
  month = sep,
  doi = {10.1172/jci188241},
  url = {https://doi.org/10.1172/jci188241},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Microtubule-associated protein 1S phosphorylation regulates dynein-driven transport and synaptogenesis in neurons
AU  - André T. Lopes
AU  - Ondine Janiv
AU  - Suzanne Claxton
AU  - Sila K. Ultanir
PY  - 2026
DA  - 2026/09/15
JO  - The Journal of Clinical Investigation
DO  - 10.1172/jci188241
UR  - https://doi.org/10.1172/jci188241
AB  - Cyclin-dependent kinase like 5 (CDKL5) is a serine-threonine kinase enriched in the mammalian brain whose loss of function causes a severe developmental and epileptic encephalopathy named CDKL5 Deficiency Disorder. We previously showed that CDKL5 phosphorylates the microtubule-associated protein MAP1S, but how this regulates microtubule-dependent functions is not well understood. To address this question, we generated MAP1S phosphomutant mice in which the CDKL5 phosphorylation sites S786 and S812 were mutated to alanine (MAP1S S786/812A; MAP1S SA). Using a microtubule cosedimentation assay, we found that dynein binding to microtubules was reduced in MAP1S SA and CDKL5 knockout (KO) brain lysates, and time-lapse imaging showed impaired dynein motility in dendrites from both genotypes. MAP1S SA mice also exhibited reduced AMPA receptor transport, dendritic spine density, and excitatory synapses, accompanied by anxiety-like behavior and motor, social, and memory deficits relevant to CDD. Mechanistically, MAP1S SA and CDKL5 KO neurons showed increased microtubule stability and reduced tubulin tyrosination, consistent with excessive MAP1S-mediated stabilization. Restoring tubulin tyrosination by expressing tubulin-tyrosine ligase rescued dynein transport defects. Together, these findings identify MAP1S phosphorylation as a critical regulator of microtubule dynamics and dynein-dependent transport.
SN  - 0021-9738
SN  - 1558-8238
ER  -