A cross-species proteomic map reveals neoteny of human synapse development

Li Wang (), Kaifang Pang, Li Zhou, Arantxa Cebrián-Silla, Susana González-Granero, Shaohui Wang, Qiuli Bi, Matthew L. White, Brandon Ho, Jiani Li, Tao Li, Yonatan Perez, Eric J. Huang, Ethan A. Winkler, Mercedes F. Paredes, Rothem Kovner, Nenad Sestan, Alex A. Pollen, Pengyuan Liu, Jingjing Li, Xianhua Piao, José Manuel García-Verdugo, Arturo Alvarez-Buylla, Zhandong Liu and Arnold R. Kriegstein ()
Additional contact information
Li Wang: University of California San Francisco
Kaifang Pang: Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital
Li Zhou: University of California San Francisco
Arantxa Cebrián-Silla: University of California San Francisco
Susana González-Granero: University of Valencia and CIBERNED
Shaohui Wang: University of California San Francisco
Qiuli Bi: University of California San Francisco
Matthew L. White: University of California San Francisco
Brandon Ho: University of California San Francisco
Jiani Li: Gilead Sciences
Tao Li: University of California San Francisco
Yonatan Perez: University of California San Francisco
Eric J. Huang: University of California San Francisco
Ethan A. Winkler: University of California San Francisco
Mercedes F. Paredes: University of California San Francisco
Rothem Kovner: Yale School of Medicine, Yale University
Nenad Sestan: Yale School of Medicine, Yale University
Alex A. Pollen: University of California San Francisco
Pengyuan Liu: University of Massachusetts Lowell
Jingjing Li: University of California San Francisco
Xianhua Piao: University of California San Francisco
José Manuel García-Verdugo: University of Valencia and CIBERNED
Arturo Alvarez-Buylla: University of California San Francisco
Zhandong Liu: Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital
Arnold R. Kriegstein: University of California San Francisco

Nature, 2023, vol. 622, issue 7981, 112-119

Abstract: Abstract The molecular mechanisms and evolutionary changes accompanying synapse development are still poorly understood1,2. Here we generate a cross-species proteomic map of synapse development in the human, macaque and mouse neocortex. By tracking the changes of more than 1,000 postsynaptic density (PSD) proteins from midgestation to young adulthood, we find that PSD maturation in humans separates into three major phases that are dominated by distinct pathways. Cross-species comparisons reveal that human PSDs mature about two to three times slower than those of other species and contain higher levels of Rho guanine nucleotide exchange factors (RhoGEFs) in the perinatal period. Enhancement of RhoGEF signalling in human neurons delays morphological maturation of dendritic spines and functional maturation of synapses, potentially contributing to the neotenic traits of human brain development. In addition, PSD proteins can be divided into four modules that exert stage- and cell-type-specific functions, possibly explaining their differential associations with cognitive functions and diseases. Our proteomic map of synapse development provides a blueprint for studying the molecular basis and evolutionary changes of synapse maturation.

Date: 2023
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DOI: 10.1038/s41586-023-06542-2

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