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 LiXianhua Piao, José Manuel García-Verdugo, Arturo Alvarez-Buylla, Zhandong Liu, Arnold R. Kriegstein

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

The molecular mechanisms and evolutionary changes accompanying synapse development are still poorly understood 1,2. 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.

Original languageEnglish
Pages (from-to)112-119
Number of pages8
JournalNature
Volume622
Issue number7981
DOIs
StatePublished - 5 Oct 2023
Externally publishedYes

ASJC Scopus subject areas

  • General

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