Protein degradation shapes developmental tempo in mouse and human neural progenitors

Abstract

The speed of embryonic development varies considerably between mammalian species, yet the underlying molecular mechanisms remain poorly understood. To investigate the basis for species-specific developmental tempo, we performed a comprehensive comparative analysis of protein dynamics in mouse and human neural progenitors (NPs). Through a combination of targeted protein labelling, quantitative mass spectrometry, and protein depletion with self-labeling tags, we demonstrate that protein degradation is a key driver of tempo differences between mouse and human NPs. We observe a systematic 1.5-fold increase in protein half-lives in human NPs compared to mouse, independent of cellular compartment or protein function. This difference persists in post-mitotic neurons, indicating active degradation as the primary mechanism. Proteasomal activity is also ∼1.5-fold higher in mouse NPs, consistent with upregulation of proteasome-associated proteins. Importantly, increasing the rate of proteolytic degradation of a key transcriptional repressor in neural progenitors accelerates the expression of its target gene. Despite differences in degradation rates, protein synthesis rates are similar between species, resulting in higher protein content in human NPs. Our findings highlight the central role of protein degradation in controlling developmental tempo and provide insight into the molecular basis of evolutionary changes in developmental timing across species.