CTNND2 moderates the pace of synaptic maturation and links human evolution to synaptic neoteny.
Cell Rep
; 43(10): 114797, 2024 Sep 30.
Article
em En
| MEDLINE
| ID: mdl-39352808
ABSTRACT
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.
CP: Developmental biology; CP: Neuroscience; CTNND2; SRGAP2; SRGAP2C; SYNGAP1; autism spectrum disorder; dendritic spine; gene duplication; human brain evolution; human-specific gene; intellectual disability; intrinsic excitability; neoteny; postsynaptic scaffold; synapse; synaptic transmission; synaptogenesis
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
Cell Rep
/
Cell reports
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
França
País de publicação:
Estados Unidos