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Peer-reviewedCC BY 4.0Nature Neuroscience

CLOK: a chemigenetic multicolor labeling system to visualize neuronal birthdate and circuit integration

  • Giulia Faini1
  • Matthieu Tuffery1
  • Amna Saleem2
  • Lixia Zhang3,4
  • Felix Du2
  • Guillaume Le Bourdelles1
  • Karine Duroure1
  • Eric R. Schreiter3
  • Dimitrii Tanese1
  • Valentina Emiliani1
  • Filippo Del Bene1
  • Minoru Koyama2,5
5 affiliations
  1. 1Institut de la Vision, Sorbonne Université, Inserm S968, CNRS UMR7210, Paris, France
  2. 2Department of Biological Sciences, University of Toronto Scarborough, Toronto, Ontario Canada
  3. 3Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA USA
  4. 4Present Address: Advanced Imaging and Microscopy Resource, National Institutes of Health, Bethesda, MD USA
  5. 5Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario Canada
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Abstract

Understanding how neurons integrate into developing circuits and contribute to functional activity is essential for decoding brain development and plasticity. However, current methods to study neuronal integration often suffer from low throughput, limited spatiotemporal resolution or invasive procedures. To overcome these challenges, here we present CLOK, an in vivo birthdate-labeling strategy based on HaloTag technology and its broad palette of fluorescent ligands. We show that CLOK enables precise color-coding of neurons and their subcellular structures by birthdate and allows tracking of functional maturation of newborn neurons in the developing zebrafish visual and motor systems, revealing distinct maturation trajectories of early- and late-born neurons. We further demonstrate the versatility of this approach by coupling it to optical tools enabling age-specific multicolor calcium and voltage imaging, as well as optogenetic manipulation. Altogether, CLOK provides a powerful and flexible tool for optical interrogation of neuronal circuit maturation in a growing and behaving vertebrate.

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Cite

BibTeXRIS
BibTeX
@article{faini2026clok,
  title = {{CLOK: a chemigenetic multicolor labeling system to visualize neuronal birthdate and circuit integration}},
  author = {Giulia Faini and Matthieu Tuffery and Amna Saleem and Lixia Zhang and Felix Du and Guillaume Le Bourdelles and Karine Duroure and Eric R. Schreiter and Dimitrii Tanese and Valentina Emiliani and Filippo Del Bene and Minoru Koyama},
  journal = {Nature Neuroscience},
  year = {2026},
  month = sep,
  doi = {10.1038/s41593-026-02423-9},
  url = {https://doi.org/10.1038/s41593-026-02423-9},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - CLOK: a chemigenetic multicolor labeling system to visualize neuronal birthdate and circuit integration
AU  - Giulia Faini
AU  - Matthieu Tuffery
AU  - Amna Saleem
AU  - Lixia Zhang
AU  - Felix Du
AU  - Guillaume Le Bourdelles
AU  - Karine Duroure
AU  - Eric R. Schreiter
AU  - Dimitrii Tanese
AU  - Valentina Emiliani
AU  - Filippo Del Bene
AU  - Minoru Koyama
PY  - 2026
DA  - 2026/09/30
JO  - Nature Neuroscience
DO  - 10.1038/s41593-026-02423-9
UR  - https://doi.org/10.1038/s41593-026-02423-9
AB  - Understanding how neurons integrate into developing circuits and contribute to functional activity is essential for decoding brain development and plasticity. However, current methods to study neuronal integration often suffer from low throughput, limited spatiotemporal resolution or invasive procedures. To overcome these challenges, here we present CLOK, an in vivo birthdate-labeling strategy based on HaloTag technology and its broad palette of fluorescent ligands. We show that CLOK enables precise color-coding of neurons and their subcellular structures by birthdate and allows tracking of functional maturation of newborn neurons in the developing zebrafish visual and motor systems, revealing distinct maturation trajectories of early- and late-born neurons. We further demonstrate the versatility of this approach by coupling it to optical tools enabling age-specific multicolor calcium and voltage imaging, as well as optogenetic manipulation. Altogether, CLOK provides a powerful and flexible tool for optical interrogation of neuronal circuit maturation in a growing and behaving vertebrate.
SN  - 1097-6256
SN  - 1546-1726
ER  -