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Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition
Baptiste Libé‐Philippot (Université Libre de Bruxelles, VIB-KU Leuven Center for Brain & Disease Research), Ryohei Iwata (Université Libre de Bruxelles, VIB-KU Leuven Center for Brain & Disease Research), Aleksandra J. Recupero (Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University), Keimpe D. B. Wierda (VIB-KU Leuven Center for Brain & Disease Research), Sergio Bernal-Garcia (Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University), Luke Alexander Hammond (Mortimer B. Zuckerman Mind Brain Behavior Institute, The Ohio State University), Anja van Benthem (Université Libre de Bruxelles), Ridha Limame (Université Libre de Bruxelles, VIB-KU Leuven Center for Brain & Disease Research), Martyna Ditkowska (VIB-KU Leuven Center for Brain & Disease Research, KU Leuven), Sofie Beckers (VIB-KU Leuven Center for Brain & Disease Research, KU Leuven), Vaiva Gaspariunaite (VIB-KU Leuven Center for Brain & Disease Research, KU Leuven), Eugénie Pezé-Heidsieck (Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University), Daan Remans (VIB-KU Leuven Center for Brain & Disease Research, KU Leuven), Cécile Charrier (Centre National de la Recherche Scientifique, Inserm), Tom Theys (KU Leuven), Franck Polleux (Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University), Pierre Vanderhaeghen (Université Libre de Bruxelles, VIB-KU Leuven Center for Brain & Disease Research)
Résumé : 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.