SRGAP2C
SLIT-ROBO Rho GTPase activating protein 2C is a protein in humans that is encoded by the SRGAP2C gene.[3]
Cortical development gene Slit-Robo Rho GTPase-activating protein 2 (SRGAP2) has been highly conserved over mammalian evolution, and human is the only lineage wherein gene duplications have occurred (three times). The promoter and first nine exons of SRGAP2 duplicated from 1q23.1 (SRGAP2A) to 1q21.1 (SRGAP2B) ~3.4 million years ago (mya). Two larger duplications later copied SRGAP2B to chromosome 1p12 (SRGAP2C) and to proximal 1q21.1 (SRGAP2D) ~2.4 and ~1 mya, respectively. Ancestral SRGAP2A and the derived SRGAP2C copy are fixed at diploid copy number two. In contrast, the SRGAP2B and SRGAP2D are highly copy number polymorphic, with normal individuals identified that completely lack these paralogscopies. SRGAP2C is the most likely duplicate to encode a functional protein and is among the most fixed human-specific duplicate genes. Incomplete duplication created a novel gene function—antagonizing parental SRGAP2 function immediately “at birth” 2–3 mya, which is a time corresponding to the transition from Australopithecus to Homo and the beginning of neocortex expansion.[4][5]
SRGAP2C is expressed in the human brain and dimerizes with ancestral SRGAP2 to antagonize it. In the mouse neocortex, SRGAP2 promotes spine maturation and limits spine density. SRGAP2C phenocopies SRGAP2 deficiency and underlies sustained radial migration and results in the emergence of human-specific features, including neoteny during spine maturation and increased density of longer spines. It appears that the SRGAP2C ultimately assumed the antagonistic function of the SRGAP2B duplicate, which shows evidence of pseudogenization in contemporary humans. It is unlikely that SRGAP2B and SRGAP2D are now functional as SRGAP2B has a markedly reduced expression in human brain compared to SRGAP2C and the transcripts produced by SRGAP2D lack two internal exons, leading to a premature termination codon.[4][6] SRGAP2B and SRGAP2C are necessary in the protracted synaptic maturation of human neurons.[7] They act on ancestral molecular pathways that involve SRGAP2 and SYNGAP1, a major gene involved in neurodevelopmental disorders.[7]
References
[edit]- ^ a b c GRCh38: Ensembl release 89: ENSG00000171943 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: SLIT-ROBO Rho GTPase activating protein 2C".
- ^ a b Charrier C, Joshi K, Coutinho-Budd J, Kim JE, Lambert N, de Marchena J, Jin WL, Vanderhaeghen P, Ghosh A, Sassa T, Polleux F (May 2012). "Inhibition of SRGAP2 function by its human-specific paralogs induces neoteny during spine maturation". Cell. 149 (4): 923–35. doi:10.1016/j.cell.2012.03.034. PMC 3357949. PMID 22559944.
- ^ Sporny, M; Guez-Haddad, J; Kreusch, A; Shakartzi, S; Neznansky, A; Cross, A; Isupov, MN; Qualmann, B; Kessels, MM; Opatowsky, Y (1 June 2017). "Structural History of Human SRGAP2 Proteins". Molecular Biology and Evolution. 34 (6): 1463–1478. doi:10.1093/molbev/msx094. PMC 5435084. PMID 28333212.
- ^ Dennis MY, Nuttle X, Sudmant PH, Antonacci F, Graves TA, Nefedov M, Rosenfeld JA, Sajjadian S, Malig M, Kotkiewicz H, Curry CJ, Shafer S, Shaffer LG, de Jong PJ, Wilson RK, Eichler EE (May 2012). "Evolution of human-specific neural SRGAP2 genes by incomplete segmental duplication". Cell. 149 (4): 912–22. doi:10.1016/j.cell.2012.03.033. PMC 3365555. PMID 22559943.
- ^ a b Baptiste Libé-Philippot, Ryohei Iwata, Aleksandra J. Recupero, Keimpe Wierda, Sergio Bernal Garcia, Luke Hammond, Anja van Benthem, Ridha Limame, Martyna Ditkowska, Sofie Beckers, Vaiva Gaspariunaite, Eugénie Peze-Heidsieck, Daan Remans, Cécile Charrier, Tom Theys, Franck Polleux, Pierre Vanderhaeghen. "Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition". Neuron. doi:10.1016/j.neuron.2024.08.021.