Cell Discovery: Jiao Jianwei's team revealed a new mechanism by which human-specific genes promote cerebral cortical folding

In the process of human evolution, the expansion of the neocortex is closely related
to the improvement of intelligence and cognitive function.
A key aspect of this expansion is the formation of the cerebral cortical sulcus gyrus, which allows the dilated cortical surface area to accommodate the limited skull space
.
These evolutionary features rely primarily on a larger number of cortical neurons produced by multiple neural stem and progenitor cell subtypes and their neurogenic
division.

In recent years, many studies have revealed that there is an important connection between external radial glial cells (oRG) and the formation of cerebral cortical gyrus, firstly, because oRG, as a large number of neural precursor cells in the human brain, increases the type and number of neural progenitor cells; Second, oRG provides more radial migration paths for neurons, thereby promoting the expansion of the cortex and the formation
of sulcus.
However, the molecular and cellular mechanisms underlying the folding of the cerebral cortex are still poorly
understood.

Recently, the research group of Jiao Jianwei of the Institute of Zoology, Chinese Academy of Sciences published a research paper
in the journal Cell Discovery: Human SERPINA3 induces neocortical folding and improves cognitive ability in mice.

The study found that the human-derived gene SERPINA3 promoted the expansion and folding of the mouse cortex, increased the number of upper neurons, and significantly improved the cognitive ability
of the mice.

The research team first constructed conditional gene knock-in mice (cKI) to overexpress SERPINA3 in the nervous system, and found that SERPINA3 can promote the proliferation of neural stem cells in the mouse brain and the production
of external radial glial cells (oRG) during neurodevelopment.
After birth, cKI mice showed the phenomenon of enlargement of cerebral cortex surface area, thickening of cortex, and formation of sulcus structure
.

Single-cell sequencing analysis of the cerebral cortex of neonatal mice further demonstrated that SERPINA3 overexpression increased the output
of upper neurons.
Adult cKI mice showed stronger learning and memory abilities in behavioral experiments than wild types
.

The study also found through transcriptome sequencing that SERPINA3 regulates its expression
by binding to the promoter of the downstream target gene Glo1.
As a key factor in regulating the metabolism of pyruvaldehyde, the expression of Glo1 accelerates the metabolism of pyruvaldehyde after upregulation, thereby promoting the proliferation of neural progenitor cells and the expansion and folding
of the cerebral cortex.

Diagram of the role of SERPINA3 in cerebral cortical expansion and folding

In summary, this study not only reveals the important role of SERPINA3 on the proliferation and abundance of neural stem cells, but also elucidates a new molecular mechanism
of cerebral cortex expansion and folding.