Human synaptic neoteny requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition

Libe-Philippot, B.; Iwata, R.; Recupero, A. J.; Wierda, K.; Ditkowska, M.; Gaspariunaite, V.; Vermaercke, B.; Peze-Heidsieck, E.; Remans, D.; Charrier, C.; Polleux, F.; Vanderhaeghen, P.

doi:10.1101/2023.03.01.530630

bioRxiv · 10.1101/2023.03.01.530630

Human synaptic neoteny requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition

Libe-Philippot, B.·Iwata, R.·Recupero, A. J.·Wierda, K.·Ditkowska, M.·Gaspariunaite, V.·Vermaercke, B.·Peze-Heidsieck, E.·Remans, D.·Charrier, C.·Polleux, F.·Vanderhaeghen, P.

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Abstract

Human-specific (HS) genes are potential drivers of brain evolution, but their impact on human neuron development and disease remains unclear. Here we studied HS genes SRGAP2B/C in human cortical projection neurons (CPNs) in vivo, using xenotransplantation in the mouse cortex. Downregulation of SRGAP2B/C in human CPNs greatly accelerated synaptic development, indicating their requirement for human-specific synaptic neoteny. SRGAP2B/C acted by downregulating their ancestral paralog SRGAP2A, thereby upregulating postsynaptic levels of SYNGAP1, a major intellectual deficiency/autism spectrum disorder (ID/ASD) gene. Combinatorial genetic invalidation revealed that the tempo of synaptogenesis is set by a balance between SRGAP2A and SYNGAP1, which in human CPNs is tipped towards neoteny by SRGAP2B/C. Our results demonstrate that HS genes can modify the phenotypic expression of ID/ASD mutations through regulation of synaptic neoteny. One-Sentence SummaryHuman-specific genes SRGAP2B/C control human cortical neuron neoteny by regulating the function of neurodevelopmental disorder gene SYNGAP1

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Libe-Philippot, B., Iwata, R., Recupero, A. J., Wierda, K., Ditkowska, M., Gaspariunaite, V., Vermaercke, B., Peze-Heidsieck, E., Remans, D., Charrier, C., Polleux, F., Vanderhaeghen, P.. 2023-03-02. Human synaptic neoteny requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition. https://doi.org/10.1101/2023.03.01.530630

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