Human-specific paralogs of SRGAP2 induce neotenic features of microglia structural and functional maturation

Diaz-Salazar, Carlos; Krzisch, Marine; Yoo, Juyoun; Nano, Patricia R.; Bhaduri, Aparna; Jaenisch, Rudolf; Polleux, Franck

doi:10.1101/2024.06.28.601266

Cited by 2 publications

References 87 publications

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Accelerated cell-type-specific regulatory evolution of the human brain

Joshy,

Santpere,

2024

Proc. Natl. Acad. Sci. U.S.A.

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The molecular basis of human brain evolution is a key piece in understanding the evolution of human-specific cognitive and behavioral traits. Comparative studies have suggested that human brain evolution was accompanied by accelerated changes of gene expression (referred to as “regulatory evolution”), especially those leading to an increase of gene products involved in energy production and metabolism. However, the signals of accelerated regulatory evolution were not always consistent across studies. One confounding factor is the diversity of distinctive cell types in the human brain. Here, we leveraged single-cell human and nonhuman primate transcriptomic data to investigate regulatory evolution at cell-type resolution. We relied on six well-established major cell types: excitatory and inhibitory neurons, astrocytes, microglia, oligodendrocytes, and oligodendrocyte precursor cells. We found pervasive signatures of accelerated regulatory evolution in the human brains compared to the chimpanzee brains in the major six cell types, as well as across multiple neuronal subtypes. Moreover, regulatory evolution is highly cell type specific rather than shared between cell types and strongly associated with cellular-level epigenomic features. Evolutionarily differentially expressed genes (DEGs) exhibit greater cell-type specificity than other genes, suggesting their role in the functional specialization of individual cell types in the human brain. As we continue to unfold the cellular complexity of the brain, the actual scope of DEGs in the human brain appears to be much broader than previously estimated. Our study supports the acceleration of cell-type-specific functional programs as an important feature of human brain evolution.

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Accelerated cell-type-specific regulatory evolution of the human brain

Joshy,

Santpere,

2024

Proc. Natl. Acad. Sci. U.S.A.

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Zebrafish models of human-duplicatedSRGAP2reveal novel functions in microglia and visual system development

Uribe-Salazar,

Kaya,

Weyenberg

et al. 2024

Preprint

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Recent expansion of duplicated genes unique in the Homo lineage likely contributed to brain evolution and other human-specific traits. One hallmark example is the expansion of the human SRGAP2 family, resulting in a human-specific paralog SRGAP2C. Introduction of SRGAP2C in mouse models is associated with altering cortical neuronal migration, axon guidance, synaptogenesis, and sensory-task performance. Truncated, human-specific SRGAP2C heterodimerizes with the full-length ancestral gene product SRGAP2A and antagonizes its functions. However, the significance of SRGAP2 duplication beyond neocortex development has not been elucidated due to the embryonic lethality of complete Srgap2 knockout in mice. Using zebrafish, we showed that srgap2 knockout results in viable offspring that phenocopy "humanized" SRGAP2C larvae. Specifically, human SRGAP2C protein interacts with zebrafish Srgap2, demonstrating similar Srgap2 functional antagonism observed in mice. Shared traits between knockout and humanized zebrafish larvae include altered morphometric features (i.e., reduced body length and inter-eye distance) and differential expression of synapse-, axogenesis-, vision-related genes. Through single-cell transcriptome analysis, we further observed a skewed balance of excitatory and inhibitory neurons that likely contributes to increased susceptibility to seizures displayed by Srgap2 mutant larvae, a phenotype resembling SRGAP2 loss-of-function in a child with early infantile epileptic encephalopathy. Single-cell data also pointed to strong microglia expression of srgap2 with mutants exhibiting altered membrane dynamics and likely delayed maturation of microglial cells. srgap2-expressing microglia cells were also detected in the developing eye together with altered expression of genes related to axogenesis and synaptogenesis in mutant retinal cells. Consistent with the perturbed gene expression in the retina, we found that SRGAP2 mutant larvae exhibited increased sensitivity to broad and fine visual cues. Finally, comparing the transcriptomes of relevant cell types between human (+SRGAP2C) and non-human primates (-SRGAP2C) revealed significant overlaps of gene alterations with mutant cells in our zebrafish models; this suggests that SRGAP2C plays similar roles altering microglia and the visual system in modern humans. Together, our functional characterization of zebrafish Srgap2 and human SRGAP2C in zebrafish uncovered novel gene functions and highlights the strength of cross-species analysis in understanding the development of human-specific features.

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Human-specific paralogs of SRGAP2 induce neotenic features of microglia structural and functional maturation

Cited by 2 publications

References 87 publications

Accelerated cell-type-specific regulatory evolution of the human brain

Accelerated cell-type-specific regulatory evolution of the human brain

Zebrafish models of human-duplicatedSRGAP2reveal novel functions in microglia and visual system development

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