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Peer-reviewedCC BY-NC-NDDevelopmental Cell

Proteasome-dependent protein degradation shapes developmental tempo in mouse and human neural progenitors

  • Shota Nakanoh1
  • Despina Stamataki2
  • Lorena Garcia-Perez2
  • Chiara Azzi1
  • Hayley L. Carr1
  • Alexandra Pokhilko1
  • Loukik Doshi1
  • Giulia L. M. Boezio2
  • Hilary Knowles2
  • Adriana Lamas Bancalari1
  • Manuela Melchionda2
  • Lu Yu1
6 more authors
  • Steven A. Howell2
  • Mark Skehel2
  • David Oxley1
  • Simon Andrews1
  • James Briscoe3
  • Teresa Rayón4
4 affiliations
  1. 1Babraham Institute, Cambridge, UK
  2. 2The Francis Crick Institute, London, UK
  3. 3The Francis Crick Institute, London, UK. Electronic address: [email protected]
  4. 4Babraham Institute, Cambridge, UK. Electronic address: [email protected]
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Abstract

The pace of embryonic development differs between mammalian species, yet the molecular basis for this remains unknown. By comparing protein dynamics in mouse and human neural progenitors (NPs), we show that protein turnover is faster in mouse NPs, driven by higher rates of protein synthesis and degradation. Human NPs exhibit longer protein half-lives, reduced proteasomal activity, and lower proteasome abundance. These differences persist in post-mitotic neurons and are also observed in the embryonic spinal cord in vivo. Pharmacological inhibition of proteasomal activity slows differentiation in mouse NPs. Conversely, enhancing proteasomal activity accelerates neuronal output in human NPs. Moreover, accelerating the degradation of the key transcriptional repressor IRX3 in mouse NPs speeds the activation of its target gene. Together, these results provide evidence that species-specific regulation of proteasome-mediated proteolysis influences the timing of neural development and suggest that evolutionary tuning of proteasomal activity contributes to differences in embryonic developmental pace.

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Cite

BibTeXRIS
BibTeX
@article{nakanoh2026proteasomedependent,
  title = {{Proteasome-dependent protein degradation shapes developmental tempo in mouse and human neural progenitors}},
  author = {Shota Nakanoh and Despina Stamataki and Lorena Garcia-Perez and Chiara Azzi and Hayley L. Carr and Alexandra Pokhilko and Loukik Doshi and Giulia L. M. Boezio and Hilary Knowles and Adriana Lamas Bancalari and Manuela Melchionda and Lu Yu and Steven A. Howell and Mark Skehel and David Oxley and Simon Andrews and James Briscoe and Teresa Rayón},
  journal = {Developmental Cell},
  year = {2026},
  month = aug,
  doi = {10.1016/j.devcel.2026.07.014},
  url = {https://doi.org/10.1016/j.devcel.2026.07.014},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Proteasome-dependent protein degradation shapes developmental tempo in mouse and human neural progenitors
AU  - Shota Nakanoh
AU  - Despina Stamataki
AU  - Lorena Garcia-Perez
AU  - Chiara Azzi
AU  - Hayley L. Carr
AU  - Alexandra Pokhilko
AU  - Loukik Doshi
AU  - Giulia L. M. Boezio
AU  - Hilary Knowles
AU  - Adriana Lamas Bancalari
AU  - Manuela Melchionda
AU  - Lu Yu
AU  - Steven A. Howell
AU  - Mark Skehel
AU  - David Oxley
AU  - Simon Andrews
AU  - James Briscoe
AU  - Teresa Rayón
PY  - 2026
DA  - 2026/08/13
JO  - Developmental Cell
DO  - 10.1016/j.devcel.2026.07.014
UR  - https://doi.org/10.1016/j.devcel.2026.07.014
AB  - The pace of embryonic development differs between mammalian species, yet the molecular basis for this remains unknown. By comparing protein dynamics in mouse and human neural progenitors (NPs), we show that protein turnover is faster in mouse NPs, driven by higher rates of protein synthesis and degradation. Human NPs exhibit longer protein half-lives, reduced proteasomal activity, and lower proteasome abundance. These differences persist in post-mitotic neurons and are also observed in the embryonic spinal cord in vivo. Pharmacological inhibition of proteasomal activity slows differentiation in mouse NPs. Conversely, enhancing proteasomal activity accelerates neuronal output in human NPs. Moreover, accelerating the degradation of the key transcriptional repressor IRX3 in mouse NPs speeds the activation of its target gene. Together, these results provide evidence that species-specific regulation of proteasome-mediated proteolysis influences the timing of neural development and suggest that evolutionary tuning of proteasomal activity contributes to differences in embryonic developmental pace.
SN  - 1534-5807
SN  - 1878-1551
ER  -