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

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.

Oligodendrocyte-specific expression of PSG8-AS1 suggests a role in myelination with prognostic value in oligodendroglioma.

The segmentally duplicated Pregnancy-specific glycoprotein (PSG) locus on chromosome 19q13 may be one of the most rapidly evolving in the human genome. It comprises ten coding genes (PSG1-9, 11) and one predominantly non-coding gene (PSG10) that are expressed in the placenta and gut, in addition to several poorly characterized long non-coding RNAs. We report that long non-coding RNA PSG8-AS1 has an oligodendrocyte-specific expression pattern and is co-expressed with genes encoding key myelin constituents. PSG8-AS1 exhibits two peaks of expression during human brain development coinciding with the most active periods of oligodendrogenesis and myelination. PSG8-AS1 orthologs were found in the genomes of several primates but significant expression was found only in the human, suggesting a recent evolutionary origin of its proposed role in myelination. Additionally, because co-deletion of chromosomes 1p/19q is a genomic marker of oligodendroglioma, expression of PSG8-AS1 was examined in these tumors. PSG8-AS1 may be a promising diagnostic biomarker for glioma, with prognostic value in oligodendroglioma.

The Principle of Cortical Development and Evolution.

Human's robust cognitive abilities, including creativity and language, are made possible, at least in large part, by evolutionary changes made to the cerebral cortex. This paper reviews the biology and evolution of mammalian cortical radial glial cells (primary neural stem cells) and introduces the concept that a genetically step wise process, based on a core molecular pathway already in use, is the evolutionary process that has molded cortical neurogenesis. The core mechanism, which has been identified in our recent studies, is the extracellular signal-regulated kinase (ERK)-bone morphogenic protein 7 (BMP7)-GLI3 repressor form (GLI3R)-sonic hedgehog (SHH) positive feedback loop. Additionally, I propose that the molecular basis for cortical evolutionary dwarfism, exemplified by the lissencephalic mouse which originated from a larger gyrencephalic ancestor, is an increase in SHH signaling in radial glia, that antagonizes ERK-BMP7 signaling. Finally, I propose that: (1) SHH signaling is not a key regulator of primate cortical expansion and folding; (2) human cortical radial glial cells do not generate neocortical interneurons; (3) human-specific genes may not be essential for most cortical expansion. I hope this review assists colleagues in the field, guiding research to address gaps in our understanding of cortical development and evolution.

Unanswered questions in the regulation and function of the duplicated α7 nicotinic receptor gene CHRFAM7A.

The α7 nicotinic receptor (α7 nAChR) is an important entry point for Ca2+ into the cell, which has broad and important effects on gene expression and function. The gene (CHRNA7), mapping to chromosome (15q14), has been genetically linked to a large number of diseases, many of which involve defects in cognition. While numerous mutations in CHRNA7 are associated with mental illness and inflammation, an important control point may be the function of a recently discovered partial duplication CHRNA7, CHRFAM7A, that negatively regulates the function of the α7 receptor, through the formation of heteropentamers; other functions cannot be excluded. The deregulation of this human specific gene (CHRFAM7A) has been linked to neurodevelopmental, neurodegenerative, and inflammatory disorders and has important copy number variations. Much effort is being made to understand its function and regulation both in healthy and pathological conditions. However, many questions remain to be answered regarding its functional role, its regulation, and its role in the etiogenesis of neurological and inflammatory disorders. Missing knowledge on the pharmacology of the heteroreceptor has limited the discovery of new molecules capable of modulating its activity. Here we review the state of the art on the role of CHRFAM7A, highlighting unanswered questions to be addressed. A possible therapeutic approach based on genome editing protocols is also discussed.

The emergence of the uniquely human α7 nicotinic acetylcholine receptor gene and its roles in inflammation.

The uniquely human CHRFAM7A gene is evolved from the fusion of two partially duplicated genes, ULK4 and CHRNA7. Transcription of CHRFAM7A gene produces a 1256-bp open reading frame (ORF) that encodes duplicate α7-nAChR (dup-α7-nAChR), in which a 27-aminoacid peptide derived from ULK4 gene replaces the 146-aminoacid N-terminal extracellular domain of α7-nAChR, and the rest protein domains are exactly the same as those of α7-nAChR. In vitro, dup-α7-nAChR has been shown to form hetero-pentamer with α7-nAChR and dominant-negatively inhibits the channel functions of the latter. α7-nAChR has been shown to participate in many pathophysiological processes such as cognition, memory, neuronal degenerative disease, psychological disease, and inflammatory diseases, among others, and thus has been extensively exploited as potential therapeutic targets for many diseases. Unfortunately, many lead compounds that showed potent therapeutic effect in preclinical animal models failed clinical trials, suggesting the possibility that the contribution of the uniquely human CHRFAM7A gene may not be accounted for in the preclinical research. Here, we review the emergence of CHRFAM7A gene and its transcriptional regulation, the regulatory roles of CHRFAM7A gene in α7-nAChR-mediated cholinergic anti-inflammatory pathway, and the potential implications of CHRFAM7A gene in translational research and drug discovery.

The Human-Restricted Isoform of the α7 nAChR, CHRFAM7A: A Double-Edged Sword in Neurological and Inflammatory Disorders.

CHRFAM7A is a relatively recent and exclusively human gene arising from the partial duplication of exons 5 to 10 of the α7 neuronal nicotinic acetylcholine receptor subunit (α7 nAChR) encoding gene, CHRNA7. CHRNA7 is related to several disorders that involve cognitive deficits, including neuropsychiatric, neurodegenerative, and inflammatory disorders. In extra-neuronal tissues, α7nAChR plays an important role in proliferation, differentiation, migration, adhesion, cell contact, apoptosis, angiogenesis, and tumor progression, as well as in the modulation of the inflammatory response through the "cholinergic anti-inflammatory pathway". CHRFAM7A translates the dupα7 protein in a multitude of cell lines and heterologous systems, while maintaining processing and trafficking that are very similar to the full-length form. It does not form functional ion channel receptors alone. In the presence of CHRNA7 gene products, dupα7 can assemble and form heteromeric receptors that, in order to be functional, should include at least two α7 subunits to form the agonist binding site. When incorporated into the receptor, in vitro and in vivo data showed that dupα7 negatively modulated α7 activity, probably due to a reduction in the number of ACh binding sites. Very recent data in the literature report that the presence of the duplicated gene may be responsible for the translational gap in several human diseases. Here, we will review the studies that have been conducted on CHRFAM7A in different pathologies, with the intent of providing evidence regarding when and how the expression of this duplicated gene may be beneficial or detrimental in the pathogenesis, and eventually in the therapeutic response, to CHRNA7-related neurological and non-neurological diseases.

Expression of human-specific ARHGAP11B in mice leads to neocortex expansion and increased memory flexibility.

Neocortex expansion during human evolution provides a basis for our enhanced cognitive abilities. Yet, which genes implicated in neocortex expansion are actually responsible for higher cognitive abilities is unknown. The expression of human-specific ARHGAP11B in embryonic/foetal mouse, ferret and marmoset neocortex was previously found to promote basal progenitor proliferation, upper-layer neuron generation and neocortex expansion during development, features commonly thought to contribute to increased cognitive abilities. However, a key question is whether this phenotype persists into adulthood and if so, whether cognitive abilities are indeed increased. Here, we generated a transgenic mouse line with physiological ARHGAP11B expression that exhibits increased neocortical size and upper-layer neuron numbers persisting into adulthood. Adult ARHGAP11B-transgenic mice showed altered neurobehaviour, notably increased memory flexibility and a reduced anxiety level. Our data are consistent with the notion that neocortex expansion by ARHGAP11B, a gene implicated in human evolution, underlies some of the altered neurobehavioural features observed in the transgenic mice, such as the increased memory flexibility, a neocortex-associated trait, with implications for the increase in cognitive abilities during human evolution.

Human-specific gene CHRFAM7A mediates M2 macrophage polarization via the Notch pathway to ameliorate hypertrophic scar formation.

Hypertrophic scars often cause great pain to patients. It is generally believed that anti-inflammatory scar therapies are the best strategies for treatment because excessive inflammation is observed in hypertrophic scar tissue. However, the results of such treatment are unsatisfactory. In recent studies, immune stimulatory therapies have been suggested to be a preferable method for ameliorating hypertrophic scars. In this study, the expression of the human-specific gene CHRFAM7A, which has been reported to be a promoter of inflammation, was found to be lower in human hypertrophic scars than in normotrophic scars. The CHRFAM7A gene was overexpressed in a hypertrophic scar mouse model using a lentivirus system. Scar fibrosis decreased in the CHRFAM7A transfection group compared to the control group, and the proportion of M2 macrophages decreased at 4 and 8 weeks after establishing the model. We also found that CHRFAM7A increased the activation of the Notch pathway, which eventually attenuated M2 polarization. In the CHRFAM7A-transfected hypertrophic scar mouse group, the number of M1 macrophages increased dramatically in the initial period. Moreover, the expression of the inflammatory gene TNFα was also increased in transfected mice. Our results demonstrate that CHRFAM7A can effectively ameliorate hypertrophic scar formation via regulation of macrophage phenotypic transition. CHRFAM7A might be a therapeutic target for hypertrophic scars.

Global proteomic profiling of the uniquely human CHRFAM7A gene in transgenic mouse brain.

The uniquely human α7-nAChR gene (CHRFAM7A) is evolved from the fusion of two partially duplicated genes, FAM7 and α7-nAChR gene (CHRNA7), and is inserted on same chromosome 15, 5' end of the CHRNA7 gene. Transcription of CHRFAM7A gene produces a 1256-bp open reading frame encoding dup-α7-nAChR, where a 27-aminoacid residues from FAM7 replaced the 146-aminoacid residues of the N-terminal extracellular ligand binding domain of α7-nAChR. In vitro, dup-α7-nAChR has been shown to form hetero-pentamer with α7-nAChR and dominant-negatively regulates the channel functions of α7-nAChR. However, the contribution of CHRFAM7A gene to the biology of α7-nAChR in the brain in vivo remains largely a matter of conjecture. CHRFAM7A transgenic mouse was created and differentially expressed proteins were profiled from the whole brain using iTRAQ-2D-LC-MS/MS proteomic technology. Proteins with a fold change of ≥1.2 or ≤0.83 and p < 0.05 were considered to be significant. Bioinformatics analysis showed that over-expression of the CHRFAM7A gene significantly modulated the proteins commonly involved in the signaling pathways of α7-nAChR-mediated neuropsychiatric disorders including Parkinson's disease, Alzheimer's disease, Huntington's disease, and alcoholism, suggesting that the CHRFAM7A gene contributes to the pathogenesis of neuropsychiatric disorders mostly likely through fine-tuning the functions of α7-nAChR in the brain.

Human-specific CHRFAM7A protects against radiotherapy-induced lacrimal gland injury by inhibiting the p38/JNK signalling pathway and oxidative stress.

Radiotherapy-induced lacrimal gland injury often causes dry eye. Oxidative stress and local inflammation are the primary consequences of radiotherapy-induced injury. The most recent research shows that the human-specific gene CHRFAM7A plays an important role in inflammation. However, the effect of CHRFAM7A on radiotherapy-induced lacrimal gland injury remains unclear. In this study, humanized mice were successfully generated via the transplantation of human peripheral blood mononuclear cells that expressed human-specific genes. After radiation, the CHRFAM7A gene was highly expressed in the lacrimal glands of humanized mice, in which it protected the function of the lacrimal gland after radiotherapy. CHRFAM7A down-regulated radiotherapy-induced inflammation by suppressing p38/JNK signalling. CHRFAM7A also inhibited oxidative stress in the haematopoietic system after radiotherapy. Further signalling pathway analyses indicated that CHRFAM7A suppressed Akt (protein kinase B, PKB) phosphorylation. CHRFAM7A may therefore be a therapeutic target in radiation-induced lacrimal gland injury.

A single splice site mutation in human-specific ARHGAP11B causes basal progenitor amplification.

The gene ARHGAP11B promotes basal progenitor amplification and is implicated in neocortex expansion. It arose on the human evolutionary lineage by partial duplication of ARHGAP11A, which encodes a Rho guanosine triphosphatase-activating protein (RhoGAP). However, a lack of 55 nucleotides in ARHGAP11B mRNA leads to loss of RhoGAP activity by GAP domain truncation and addition of a human-specific carboxy-terminal amino acid sequence. We show that these 55 nucleotides are deleted by mRNA splicing due to a single C→G substitution that creates a novel splice donor site. We reconstructed an ancestral ARHGAP11B complementary DNA without this substitution. Ancestral ARHGAP11B exhibits RhoGAP activity but has no ability to increase basal progenitors during neocortex development. Hence, a single nucleotide substitution underlies the specific properties of ARHGAP11B that likely contributed to the evolutionary expansion of the human neocortex.