Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition
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.
Authors
- Ridha Limame (ORCID: https://orcid.org/0000-0002-9089-4858)
- Franck Polleux (ORCID: https://orcid.org/0000-0003-4313-0481)
- Sofie Beckers (ORCID: https://orcid.org/0000-0002-0008-3753)
- Daan Remans (ORCID: https://orcid.org/0000-0003-4887-6522)
- Ryohei Iwata (ORCID: https://orcid.org/0000-0001-7371-3157)
- Tom Theys (ORCID: https://orcid.org/0000-0001-7595-3234)
- Martyna Ditkowska (ORCID: https://orcid.org/0000-0002-8524-747X)
- Baptiste Libé‐Philippot (ORCID: https://orcid.org/0000-0001-8283-804X)
- Aleksandra J. Recupero (ORCID: https://orcid.org/0000-0002-3321-4385)
- Pierre Vanderhaeghen (ORCID: https://orcid.org/0000-0001-7899-5720)
- A. van Benthem
- Vaiva Gaspariunaite (ORCID: https://orcid.org/0000-0003-2541-8377)
- Cécile Charrier (ORCID: https://orcid.org/0000-0002-9053-1715)
- Eugénie Pezé-Heidsieck
- Luke A. Hammond (ORCID: https://orcid.org/0000-0002-4065-7619)
- Keimpe Wierda (ORCID: https://orcid.org/0000-0002-8784-9490)
- Sergio Bernal Garcia
Institutions
- Centre National de la Recherche Scientifique (FR)
- Université Libre de Bruxelles (BE)
- Inserm (FR)
- École Normale Supérieure - PSL (FR)
- Institut de Biologie de l'École Normale Supérieure (FR)
Publication Details
- Journal
- Neuron
- Published
- 2024-10-14
- DOI
- https://doi.org/10.1016/j.neuron.2024.08.021
- Citations
- 15
- Primary Topic
- Neuroscience and Neuropharmacology Research
- Type
- article
- Field-Weighted Citation Impact
- 4.02
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 General Medical Sciences
- H2020 European Research Council