Abstract
Human-specific gene duplications (HSGDs) have recently emerged as key modifiers of brain development and evolution. However, the molecular mechanisms underlying the function of HSGDs remain often poorly understood. In humans, a truncated duplication of SRGAP2A led to the emergence of two human-specific paralogs: SRGAP2B and SRGAP2C. The ancestral copy SRGAP2A limits synaptic density and promotes maturation of both excitatory (E) and inhibitory (I) synapses received by cortical pyramidal neurons (PNs). SRGAP2C binds to and inhibits all known functions of SRGAP2A leading to an increase in E and I synapse density and protracted synapse maturation, traits characterizing human cortical neurons. Here, we demonstrate how the evolutionary changes that led to the emergence of SRGAP2 HSGDs generated proteins that, in neurons, are intrinsically unstable and, upon hetero-dimerization with SRGAP2A, reduce SRGAP2A levels in a proteasome-dependent manner. Moreover, we show that, despite only a few non-synonymous mutations specifically targeting arginine residues, SRGAP2C is unique compared to SRGAP2B in its ability to induce long-lasting changes in synaptic density throughout adulthood. These mutations led to the ability of SRGAP2C to inhibit SRGAP2A function and thereby contribute to the emergence of human-specific features of synaptic development during evolution.
Highlights
Previous work has demonstrated how during human evolution, gene duplication of SLIT-ROBO Rho-GTPase-activating protein 2 (SRGAP2A), which is highly expressed in the developing brain of all mammals[12,13], resulted in emergence of the human-specific paralogs SRGAP2B and SRGAP2C8,14
Human-specific partial duplication of SRGAP2A resulted in the emergence of two truncated paralogs (SRGAP2B and SRGAP2C) which both encode for a truncated protein consisting of the F-BARx domain of SRGAP2A lacking the last C-terminal 49 amino acids[6,8] (F-BARΔ49; Fig. 1)
In order to investigate whether the Δ49 truncation caused the formation of similar aggregates in neurons, we generated a construct in which we reintroduced these 49 amino acids and compared it to F-BARx with the Δ49 truncation (F-BARΔ49), and SRGAP2C
Summary
Previous work has demonstrated how during human evolution, gene duplication of SLIT-ROBO Rho-GTPase-activating protein 2 (SRGAP2A), which is highly expressed in the developing brain of all mammals[12,13], resulted in emergence of the human-specific paralogs SRGAP2B and SRGAP2C8,14. Both are truncated open reading frames (including only the first 9 exons out of 22 in Srgap2a) leading to the expression of a truncated protein corresponding to the extended F-BAR domain (F-BARx), that lacks the last C-terminal 49 amino acids (F-BARΔ49) of SRGAP2A’s FBARx domain and replaces them with 7 unique C-terminal amino acids (Fig. 1B). These results show how the emergence of the human-specific paralog SRGAP2C directly impacted the ancestral copy SRGAP2A, a critical regulator of synaptic development during human brain evolution
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