Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition
Year: 2024
Type: article
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.
Source: Neuron
Authors: Baptiste Libé-Philippot, Ryohei Iwata, Aleksandra J. Recupero, Keimpe Wierda, Sergio Bernal Garcia, Luke Hammond, Anja van Benthem, Ridha Limame, Martyna Ditkowska, Sofie Beckers, Vaiva Gaspariunaite, Eugénie Peze-Heidsieck, Daan Remans, Cécile Charrier, Tom Theys, Franck Polleux, Pierre Vanderhaeghen
Institutions: Université Libre de Bruxelles, VIB-KU Leuven Center for Brain & Disease Research, Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, The Ohio State University, KU Leuven, Centre National de la Recherche Scientifique, Inserm, Université Paris Sciences et Lettres, École Normale Supérieure - PSL, Institut de Biologie de l'École Normale Supérieure
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $9,350
Funders: Institut National de la Santé et de la Recherche Médicale, National Science Council, Fonds De La Recherche Scientifique - FNRS, Fonds Wetenschappelijk Onderzoek, KU Leuven, Centre National de la Recherche Scientifique, NOMIS Stiftung, National Institutes of Health, National Institute of Mental Health, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, H2020 European Research Council
OpenAlex ID: W4403394711