CD: Jiao Jianwei's team at the Chinese Academy of Sciences found that proteins derived from humans can induce neocortical folding and improve cognitive performance in mice

The expansion and folding of the neocortex is related to human intelligence and cognition, but the molecular and cellular mechanisms behind cortical folding are still poorly
understood.

On November 21, 2022, Jiao Jianwei's team from the Institute of Zoology, Chinese Academy of Sciences published an online title in Cell Discovery (IF=38).
The research paper "Human SERPINA3 induces neocortical folding and improves cognitive ability in mice," which showed that human SERPINA3 can induce neocortical folding and improve cognitive performance
in mice.
The study reported that the human gene SERPINA3 is associated
with gyration.
Specifically, overexpression of SERPINA3 induced neocortical folding, increased the abundance of neurons, and improved cognitive performance
.

SERPINA3 promotes the proliferation of exoradial glial cells (oRGs, also known as basal radial glial cells) and increases the number of
upper neurons.
The downstream target Glo1 was identified as involved in SERPINA3-induced gyration
.
In addition, SERPINA3 promotes the proliferation
of oRG by binding to the Glo1 promoter.
Behavioral performance assessment showed cognitive enhancement
in SERPINA3-knocked mice.
Together, the study's findings will enrich the understanding of neocortical dilation and gyru, and provide insights
into possible treatments for intellectual disability and anencephaly syndrome.

During human evolution, the expansion of the neocortex allowed for higher intellectual abilities and better cognitive function
.
A key aspect of this expansion is the formation of gyru, which allows the cortical surface area to be expanded to accommodate the limited space of the skull
.
These evolutionary features reflect the higher number
of cortical neurons produced by various nerve stem and progenitor cell subtypes and their neurogenic division.
Recent studies have shown that a subventricular region (oSVZ) has emerged in the primate cortex, consisting of a large number of proliferating exoradial glial cells (oRGs), intermediate progenitor cells (IPs), and post-mitosis neurons.

oRG cells are thought to be the main cause of
cortical folding in brain species.
To support this hypothesis, some studies have shown that oRG is associated
with cortical folding in different species.
Downregulation of Trnp1 expression leads to increased oRG production and subsequent gyration
in the cerebral cortex.
In addition, overexpression of ARHGAP11B, TBC1D3, and TMEM14B promotes the expansion of basal progenitor cells (BPs), resulting in cortical gyration in natural brainless mice or anencephaly martens
。 However, the cellular and molecular mechanisms that control the development of oRG cells and oSVZ, and the potential of these mechanisms to drive neocortical folding, are not fully understood
.

Adult cKIf/+ mice continue to expand the neocortex and increase the number of cortical neurons (Figure from Cell Discovery).

Recent studies have found that there are many evolutionary differences
in gene expression between the groomed mouse neocortex and the human fetal neocortex during embryonic development.
Genes that are expressed in human ventricle RG (vRG) and oRG, but are not expressed or are underexpressed during neurogenesis in mice, are more likely to be associated with
cortical expansion.
The authors previously searched existing detailed single-cell transcriptome datasets of vRG, oRG, IP cells, and neurons and found that the human gene SERPINA3 is one such potential candidate
。

Human SERPINA3 has 61% homology
with mouse Serpina3n.
In addition, SERPINA3 is highly expressed in radial glial cells, but Serpina3n is not expressed
in the brain during mouse neurodevelopment.
Therefore, this result suggests that SERPINA3 may be associated with
neocortical development.
Most research on SERPINA3 is limited to its inhibitory function and mechanism of serine proteases, but some studies have shown that it also acts as
a transcriptional regulator.
The study reported a novel role
in the transcriptional regulation of genes related to neurogenesis.

In this study, overexpression of SERPINA3 in the neocortex of embryonic mice promoted BPs production and self-renewal and further increased cortical thickness and induced gyration
.
Single-cell RNA sequencing (sc-RNA Seq) confirmed an increase in
upper-layer neurons in the upper cortex of SERPINA3-conditioned knock-in mice.
In addition, SERPINA3 conditioned knock-in mice showed enhanced learning and memory on behavioral tests
.
These results suggest that human SERPINA3 expression in mice is associated
with cortical expansion and cognitive enhancement.
Interestingly, the study found that SERPINA3 promotes the expression of Glo1 as a transcription factor or cofactor, and Glo1 was previously found to be involved in the proliferation of BPs2
。

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