CTNND2 moderates the pace of synaptic maturation and links human evolution to synaptic neoteny
Nora Assendorp,
Matteo Fossati,
Baptiste Libé-Philippot,
Eirini Christopoulou,
Marine Depp,
Roberta Rapone,
Florent Dingli,
Damarys Loew,
Pierre Vanderhaeghen,
Cécile Charrier
Affiliations
Nora Assendorp
Institut de Biologie de l’ENS (IBENS), Ecole Normale Supérieure, CNRS, INSERM, PSL Research University, 75005 Paris, France
Matteo Fossati
Institut de Biologie de l’ENS (IBENS), Ecole Normale Supérieure, CNRS, INSERM, PSL Research University, 75005 Paris, France
Baptiste Libé-Philippot
VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; Department of Neurosciences, Leuven Brain Institute, KUL, 3000 Leuven, Belgium
Eirini Christopoulou
Institut de Biologie de l’ENS (IBENS), Ecole Normale Supérieure, CNRS, INSERM, PSL Research University, 75005 Paris, France
Marine Depp
Institut de Biologie de l’ENS (IBENS), Ecole Normale Supérieure, CNRS, INSERM, PSL Research University, 75005 Paris, France
Roberta Rapone
Institut de Biologie de l’ENS (IBENS), Ecole Normale Supérieure, CNRS, INSERM, PSL Research University, 75005 Paris, France
Florent Dingli
Institut Curie, PSL Research University, CurieCore Tech Mass Spectrometry Proteomics, 75005 Paris, France
Damarys Loew
Institut Curie, PSL Research University, CurieCore Tech Mass Spectrometry Proteomics, 75005 Paris, France
Pierre Vanderhaeghen
VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium; Department of Neurosciences, Leuven Brain Institute, KUL, 3000 Leuven, Belgium
Cécile Charrier
Institut de Biologie de l’ENS (IBENS), Ecole Normale Supérieure, CNRS, INSERM, PSL Research University, 75005 Paris, France; Corresponding author
Summary: Human-specific genes are potential drivers of brain evolution. Among them, SRGAP2C has contributed to the emergence of features characterizing human cortical synapses, including their extended period of maturation. SRGAP2C inhibits its ancestral copy, the postsynaptic protein SRGAP2A, but the synaptic molecular pathways differentially regulated in humans by SRGAP2 proteins remain largely unknown. Here, we identify CTNND2, a protein implicated in severe intellectual disability (ID) in Cri-du-Chat syndrome, as a major partner of SRGAP2. We demonstrate that CTNND2 slows synaptic maturation and promotes neuronal integrity. During postnatal development, CTNND2 moderates neuronal excitation and excitability. In adults, it supports synapse maintenance. While CTNND2 deficiency is deleterious and results in synaptic loss of SYNGAP1, another major ID-associated protein, the human-specific protein SRGAP2C, enhances CTNND2 synaptic accumulation in human neurons. Our findings suggest that CTNND2 regulation by SRGAP2C contributes to synaptic neoteny in humans and link human-specific and ID genes at the synapse.
