Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition.

Autor:	Libé-Philippot B; VIB-KULeuven Center for Brain & Disease Research, 3000 Leuven, Belgium; Department of Neurosciences, Leuven Brain Institute, KUL, 3000 Leuven, Belgium; Université Libre de Bruxelles (ULB), Institute for Interdisciplinary Research (IRIBHM), 1070 Brussels, Belgium., Iwata R; VIB-KULeuven Center for Brain & Disease Research, 3000 Leuven, Belgium; Department of Neurosciences, Leuven Brain Institute, KUL, 3000 Leuven, Belgium; Université Libre de Bruxelles (ULB), Institute for Interdisciplinary Research (IRIBHM), 1070 Brussels, Belgium., Recupero AJ; Department of Neuroscience, Columbia University, New York, NY, USA; Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA., Wierda K; VIB-KULeuven Center for Brain & Disease Research, 3000 Leuven, Belgium; Electrophysiology Unit, VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium., Bernal Garcia S; Department of Neuroscience, Columbia University, New York, NY, USA; Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA., Hammond L; Department of Neuroscience, Columbia University, New York, NY, USA; Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA; Department of Neurology, The Ohio State University, Wexner Medical School, Columbus, OH, USA., van Benthem A; Université Libre de Bruxelles (ULB), Institute for Interdisciplinary Research (IRIBHM), 1070 Brussels, Belgium., Limame R; VIB-KULeuven Center for Brain & Disease Research, 3000 Leuven, Belgium; Department of Neurosciences, Leuven Brain Institute, KUL, 3000 Leuven, Belgium; Université Libre de Bruxelles (ULB), Institute for Interdisciplinary Research (IRIBHM), 1070 Brussels, Belgium., Ditkowska M; VIB-KULeuven Center for Brain & Disease Research, 3000 Leuven, Belgium; Department of Neurosciences, Leuven Brain Institute, KUL, 3000 Leuven, Belgium., Beckers S; VIB-KULeuven Center for Brain & Disease Research, 3000 Leuven, Belgium; Department of Neurosciences, Leuven Brain Institute, KUL, 3000 Leuven, Belgium., Gaspariunaite V; VIB-KULeuven Center for Brain & Disease Research, 3000 Leuven, Belgium; Department of Neurosciences, Leuven Brain Institute, KUL, 3000 Leuven, Belgium., Peze-Heidsieck E; Department of Neuroscience, Columbia University, New York, NY, USA; Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA., Remans D; VIB-KULeuven Center for Brain & Disease Research, 3000 Leuven, Belgium; Department of Neurosciences, Leuven Brain Institute, KUL, 3000 Leuven, Belgium., Charrier C; Institut de Biologie de l'École Normale Supérieure (IBENS), CNRS, Inserm, École Normale Supérieure, PSL Research University, Paris 75005, France., Theys T; Department of Neurosciences, Leuven Brain Institute, KUL, 3000 Leuven, Belgium; Research Group Experimental Neurosurgery and Neuroanatomy, KUL, 3000 Leuven, Belgium., Polleux F; Department of Neuroscience, Columbia University, New York, NY, USA; Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA., Vanderhaeghen P; VIB-KULeuven Center for Brain & Disease Research, 3000 Leuven, Belgium; Department of Neurosciences, Leuven Brain Institute, KUL, 3000 Leuven, Belgium; Université Libre de Bruxelles (ULB), Institute for Interdisciplinary Research (IRIBHM), 1070 Brussels, Belgium. Electronic address: pierre.vanderhaeghen@kuleuven.be.
Jazyk:	angličtina
Zdroj:	Neuron [Neuron] 2024 Nov 06; Vol. 112 (21), pp. 3602-3617.e9. Date of Electronic Publication: 2024 Oct 14.
DOI:	10.1016/j.neuron.2024.08.021
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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