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

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.