1. Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition.
- Author
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Libé-Philippot, Baptiste, Iwata, Ryohei, Recupero, Aleksandra J., Wierda, Keimpe, Bernal Garcia, Sergio, Hammond, Luke, van Benthem, Anja, Limame, Ridha, Ditkowska, Martyna, Beckers, Sofie, Gaspariunaite, Vaiva, Peze-Heidsieck, Eugénie, Remans, Daan, Charrier, Cécile, Theys, Tom, Polleux, Franck, and Vanderhaeghen, Pierre
- Abstract
Human-specific (HS) genes have been implicated in brain evolution, but their impact on human neuron development and diseases remains unclear. Here, we study SRGAP2B/C, two HS gene duplications of the ancestral synaptic gene SRGAP2A, in human cortical pyramidal neurons (CPNs) xenotransplanted in the mouse cortex. Downregulation of SRGAP2B/C in human CPNs led to strongly accelerated synaptic development, indicating their requirement for the neoteny that distinguishes human synaptogenesis. SRGAP2B/C genes promoted neoteny by reducing the synaptic levels of SRGAP2A,thereby increasing the postsynaptic accumulation of the SYNGAP1 protein, encoded by a major intellectual disability/autism spectrum disorder (ID/ASD) gene. Combinatorial loss-of-function experiments in vivo revealed that the tempo of synaptogenesis is set by the reciprocal antagonism between SRGAP2A and SYNGAP1, which in human CPNs is tipped toward neoteny by SRGAP2B/C. Thus, HS genes can modify the phenotypic expression of genetic mutations leading to ID/ASD through the regulation of human synaptic neoteny. [Display omitted] • Human-specific genes SRGAP2B/C are required for human cortical neuron neoteny • SRGAP2B/C slow down synaptogenesis by increasing the synaptic levels of SYNGAP1 • A tug of war between synaptic SRGAP2A and SYNGAP1 sets the tempo of synaptogenesis • SRGAP2B/C act as genetic modifiers of the function of SYNGAP1, encoded by a major ID/ASD gene Libé-Philippot et al. investigate the mechanisms underlying the prolonged synaptic development characteristic of human cortical neurons. They demonstrate that the human-specific genes SRGAP2B/C are required for human synaptic neoteny in vivo. They find that SRGAP2B/C slow down synaptogenesis by upregulating the synaptic levels of SYNGAP1, encoded by a major intellectual disability gene. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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