Proteasome-dependent protein degradation shapes developmental tempo in mouse and human neural progenitors
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Shota Nakanoh Despina Stamataki Lorena Garcia-Perez Chiara Azzi Hayley L Carr Alexandra Pokhilko Loukik Doshi Giulia Boezio Hilary Knowles Adriana Lamas Bancalari Manuela Melchionda Lu Yu Steven Howell Mark Skehel David Oxley Simon Andrews James Briscoe Teresa Rayon AlonsoAbstract
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.
Journal details
Journal
Developmental Cell
Volume
61
Issue number
9
Pages
1867-1882.e8
Available online
Publication date
Full text links
Publisher website (DOI)
10.1016/j.devcel.2026.07.014
Figshare
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Europe PubMed Central
42594861
Pubmed
42594861
Publishing history
The publication was previously a preprint.
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