SRGAP2 and Its Human-Specific Paralog Co-Regulate the Development of Excitatory and Inhibitory Synapses

Fossati, Matteo; Pizzarelli, Rocco; Schmidt, Ewoud R.E.; Kupferman, Justine V.; Stroebel, David; Polleux, Franck; Charrier, Cécile

doi:10.1016/j.neuron.2016.06.013

Cited by 110 publications

(142 citation statements)

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“…Human SRGAP2A is orthologous to murine Srgap2 , whereas human SRGAP2C and SRGAP2B are truncated paralogs containing only a partial F‐BAR domain . SRGAP2C can dimerize with SRGAP2A and inhibit its function . The expression of SRGAP2 paralogs in human osteoclastic cells has yet to be determined.…”

Section: Discussionmentioning

confidence: 99%

Rac1 Inhibition Via Srgap2 Restrains Inflammatory Osteoclastogenesis and Limits the Clastokine, SLIT3

Shin

Kupferman

Schmidt

et al. 2019

Journal of Bone and Mineral Research

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The Rac1‐specific guanosine triphosphatase (GTPase)‐activating protein Slit‐Robo GAP2 (Srgap2) is dramatically upregulated during RANKL‐induced osteoclastogenesis. Srgap2 interacts with the cell membrane to locally inhibit activity of Rac1. In this study, we determined the role of Srgap2 in the myeloid lineage on bone homeostasis and the osteoclastic response to TNFα treatment. The bone phenotype of mice specifically lacking Srgap2 in the myeloid lineage (Srgap2 f/f:LysM‐Cre; Srgap2 conditional knockout [cKO]) was investigated using histomorphometric analysis, in vitro cultures and Western blot analysis. Similar methods were used to determine the impact of TNFα challenge on osteoclast formation in Srgap2 cKO mice. Bone parameters in male Srgap2 cKO mice were unaffected. However, female cKO mice displayed higher trabecular bone volume due to increased osteoblast surface and bone formation rate, whereas osteoclastic parameters were unaltered. In vitro, cells from Srgap2 cKO had strongly enhanced Rac1 activation, but RANKL‐induced osteoclast formation was unaffected. In contrast, conditioned medium from Srgap2 cKO osteoclasts promoted osteoblast differentiation and had increased levels of the bone anabolic clastokine SLIT3, providing a possible mechanism for increased bone formation in vivo. Rac1 is rapidly activated by the inflammatory cytokine TNFα. Supracalvarial injection of TNFα caused an augmented osteoclastic response in Srgap2 cKO mice. In vitro, cells from Srgap2 cKO mice displayed increased osteoclast formation in response to TNFα. We conclude that Srgap2 plays a prominent role in limiting osteoclastogenesis during inflammation through Rac1, and restricts expression of the paracrine clastokine SLIT3, a positive regulator of bone formation. © 2019 American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 99%

Rac1 Inhibition Via Srgap2 Restrains Inflammatory Osteoclastogenesis and Limits the Clastokine, SLIT3

Shin

Kupferman

Schmidt

et al. 2019

Journal of Bone and Mineral Research

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“…After the divergence of human and chimpanzee lineages, SRGAP2 underwent a series of duplications in humans, with one duplication fixed across all human populations studied (Dennis et al, 2012). Interestingly, experiments in mouse suggest that this human-specific paralog interferes with the function of the ancestral copy of SRGAP2 , antagonizing its role in synapse regulation, maturation, and density, resulting in protracted synapse maturation, increased synaptic density in neocortical pyramidal neurons, and prolonged spine maturation (Fossati et al, 2016; Charrier et al, 2012). …”

Section: Protein-coding Mutationsmentioning

confidence: 99%

Evolution of the Human Nervous System Function, Structure, and Development

Sousa

Meyer

Santpere

et al. 2017

Cell

355

265

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SUMMARY The nervous system—in particular, the brain and its cognitive abilities—is among humans’ most distinctive and impressive attributes. How the nervous system has changed in the human lineage and how it differs from that of closely related primates is not well understood. Here, we consider recent comparative analyses of extant species that are uncovering new evidence for evolutionary changes in the size and the number of neurons in the human nervous system, as well as the cellular and molecular reorganization of its neural circuits. We also discuss the developmental mechanisms and underlying genetic and molecular changes that generate these structural and functional differences. As relevant new information and tools materialize at an unprecedented pace, the field is now ripe for systematic and functionally relevant studies of the development and evolution of human nervous system specializations.

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“…Interestingly, expression of SRGAP2C in mouse cortical pyramidal neurons leads to the emergence of human-specific traits of synaptic development, including an increase in synaptic density and protracted synaptic maturation of both excitatory and inhibitory synapses [6,7]. This phenotype is strikingly similar to that of a constitutive knockout mouse in which Srgap2a expression is genomically reduced, strongly suggesting that human-specific SRGAP2C functions largely by inhibiting SRGAP2A function (Charrier et al 2012).…”

Section: Introductionmentioning

confidence: 95%

“…However, knowledge of how these human-specific genetic modifications impact corresponding molecular pathways is still lacking. For example, multiple human-specific gene duplications (HSGD) have recently been identified to play a role in controlling human brain development [2][3][4][5][6][7][8][9][10][11]. However, how these genetic modifiers affect specific signaling pathways in the developing or adult human brain remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

“…This phenotype is strikingly similar to that of a constitutive knockout mouse in which Srgap2a expression is genomically reduced, strongly suggesting that human-specific SRGAP2C functions largely by inhibiting SRGAP2A function (Charrier et al 2012). Interestingly, the ancestral copy SRGAP2A limits E and I synapse density through its Rac1-specific GAP domain, while promoting maturation of both E and I synapses through its ability to bind to the postsynaptic scaffolding protein Homer1 at E synapses through its class II EVH1 binding domain embedded in its F-BAR domain, and the postsynaptic protein Gephyrin through its SH3 domain at I synapses, respectively [6,7,16,17] (Fig 1A). Because SRGAP2C directly binds SRGAP2A through its truncated F-BAR domain, we previously hypothesized that this binding directly inhibits the function of SRGAP2A [6].…”

Section: Introductionmentioning

confidence: 99%

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The human-specific paralogs SRGAP2B and SRGAP2C differentially modulate SRGAP2A-dependent synaptic development

Schmidt

Kupferman

Stackmann

et al. 2019

Preprint

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Human-specific gene duplications (HSGD) 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 HSGD generated proteins that, in neurons, are intrinsically unstable and upon hetero-dimerization with SRGAP2A, reduces SRGAP2A levels in a proteasome-dependent manner. Moreover, we show that, compared to SRGAP2B, and 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. The non-synonymous mutations specifically targeting arginine residues led to the unique ability of SRGAP2C to inhibit SRGAP2A function and thereby contribute to the emergence of human-specific features of synaptic development during evolution.

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SRGAP2 and Its Human-Specific Paralog Co-Regulate the Development of Excitatory and Inhibitory Synapses

Cited by 110 publications

References 63 publications

Rac1 Inhibition Via Srgap2 Restrains Inflammatory Osteoclastogenesis and Limits the Clastokine, SLIT3

Rac1 Inhibition Via Srgap2 Restrains Inflammatory Osteoclastogenesis and Limits the Clastokine, SLIT3

Evolution of the Human Nervous System Function, Structure, and Development

The human-specific paralogs SRGAP2B and SRGAP2C differentially modulate SRGAP2A-dependent synaptic development

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