SRGAP2C

Last update 23 Jan 2025

Basic Info

Synonyms

SLIT-ROBO Rho GTPase activating protein 2 pseudogene 1, SLIT-ROBO Rho GTPase activating protein 2C, SLIT-ROBO Rho GTPase-activating protein 2C

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Introduction

Human-specific protein that acts as a key modifier of cortical connectivity in the human brain (PubMed:22559944, PubMed:27373832, PubMed:34707291). Acts by inhibiting the functions of ancestral paralog SRGAP2/SRGAP2A, a postsynaptic protein that regulates excitatory and inhibitory synapse maturation and density in cortical pyramidal neurons (PubMed:22559944, PubMed:27373832). SRGAP2C is unstable but is able to heterodimerize with SRGAP2/SRGAP2A, thereby reducing SRGAP2/SRGAP2A levels through proteasome-dependent degradation (PubMed:27373832, PubMed:28333212, PubMed:31822692). Inhibition of SRGAP2/SRGAP2A by SRGAP2C leads to an increase in synaptic density and protracted synaptic maturation of both excitatory and inhibitory synapses (PubMed:27373832, PubMed:34707291). Modifies cortical circuit connectivity by increasing the number of local and long-range cortical inputs received by layer 2/3 pyramidal neurons (PubMed:34707291). Also able to increase the probability of sensory-evoked responses by layer 2/3 pyramidal neurons (PubMed:34707291).

100 Clinical Results associated with SRGAP2C

100 Translational Medicine associated with SRGAP2C

0 Patents (Medical) associated with SRGAP2C

Literatures (Medical) associated with SRGAP2C

01 Nov 2024·Neuron

Rev or restrain: Mechanisms of human-specific synaptic neoteny

Article

Author: Wallace, Jenelle L. ; Pollen, Alex A. ; Pollen, Alex A ; Wallace, Jenelle L

In the current issues of Neuron and Cell Reports, Libé-Philippot et al.¹ and Assendorp et al.² identify interactions between human-specific SRGAP2C, synaptic regulator SRGAP2A, and neurodevelopmental disorder-associated proteins SYNGAP1 and CTNND2 that slow synaptic maturation in human neurons.

01 Oct 2024·Cell Reports

CTNND2 moderates the pace of synaptic maturation and links human evolution to synaptic neoteny

Article

Author: Fossati, Matteo ; Dingli, Florent ; Loew, Damarys ; Libé-Philippot, Baptiste ; Christopoulou, Eirini ; Depp, Marine ; Rapone, Roberta ; Assendorp, Nora ; Charrier, Cécile ; Vanderhaeghen, Pierre

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.

09 Oct 2023·National Science Review

Brain developmental and cortical connectivity changes in transgenic monkeys carrying the human-specific duplicated gene SRGAP2C

Article

Author: Luo, Xin ; Jiang, Jin ; Chen, Kaimin ; Lin, Qiang ; Meng, Xiaoyu ; Hu, Yan ; Li, Min ; Zeng, Xuerui ; Wu, Haixu ; Liu, Cirong ; Su, Bing

ABSTRACTHuman-specific duplicated genes contributed to phenotypic innovations during the origin of our own species, such as an enlarged brain and highly developed cognitive abilities. While prior studies on transgenic mice carrying the human-specific SRGAP2C gene have shown enhanced brain connectivity, the relevance to humans remains unclear due to the significant evolutionary gap between humans and rodents. In this study, to investigate the phenotypic outcome and underlying genetic mechanism of SRGAP2C, we generated transgenic cynomolgus macaques (Macaca fascicularis) carrying the human-specific SRGAP2C gene. Longitudinal MRI imaging revealed delayed brain development with region-specific volume changes, accompanied by altered myelination levels in the temporal and occipital regions. On a cellular level, the transgenic monkeys exhibited increased deep-layer neurons during fetal neurogenesis and delayed synaptic maturation in adolescence. Moreover, transcriptome analysis detected neotenic expression in molecular pathways related to neuron ensheathment, synaptic connections, extracellular matrix and energy metabolism. Cognitively, the transgenic monkeys demonstrated improved motor planning and execution skills. Together, our findings provide new insights into the mechanisms by which the newly evolved gene shapes the unique development and circuitry of the human brain.

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SRGAP2C

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