van Roy, F. | Search bioRxiv

bioRxiv2024

Olduvai domain expression downregulates mitochondrial pathways: implications for human brain evolution and neoteny

Olduvai (formerly DUF1220) protein domains, encoded by the NBPF gene family, have undergone the greatest human lineage-specific copy-number expansion of any coding sequence in the genome and strongly correlate with brain size and neuron number across primates. Here we show that Olduvai domains act in a dosage-dependent manner to suppress mitochondrial metabolism. Transcriptomic, proteomic, and live-cell imaging analyses of cells overexpressing NBPF1 (which encodes seven Olduvai domains) reveal pronounced downregulation of mitochondrial pathways, including electron transport chain components and NADH dehydrogenase activity, as well as reduced mitochondrial abundance. By limiting energy availability, this suppression delays cellular maturation and developmental timing. We propose that the resulting prolongation of neurogenesis increases neuron production, providing a mechanistic link between Olduvai copy number expansion and the evolutionary enlargement of the human brain. This dosage-sensitive mitochondrial regulation may also contribute to broader neotenic features of human development, offering a unifying molecular mechanism for brain expansion and the neotenic traits that distinguish humans from other primates.

genomics↗

bioRxiv2019

N-cadherin stabilises neural identity by dampening anti-neural signals

A switch from E-to N-cadherin regulates the transition from pluripotency to neural identity but the mechanism by which cadherins regulate differentiation was previously unknown. Here we show that the acquisition of N-cadherin stabilises neural identity by dampening anti-neural signals. We use quantitative image-analysis to identify an effect of N-cadherin to promote neural differentiation independently of effects on cell cohesiveness. We reveal that cadherin switching diminishes the level of nuclear {beta}-catenin, and that N-cadherin also dampens FGF activity and consequently stabilises neural fate. Finally, we compare the timing of cadherin switching and differentiation in vivo and in vitro, and find that this process becomes dysregulated during in vitro differentiation. We propose that N-cadherin helps to propagate a stable neural identity throughout the emerging neuroepithelium, and that dysregulation of this process contributes to asynchronous differentiation in culture.

developmental biology↗