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Written by Zhao Jinyue, edited by Wang Sizhen In the process of human evolution, the expansion of the neocortex may enhance our cognitive ability [1-4]
.
Many genes are related to the expansion of the neocortex, because they have been shown to increase the proliferation and abundance of basal progenitor (BP) cells, thereby promoting the production of cortical neurons [5-9]
.
Among them, ARHGAP11B is a gene unique to humans
.
In the developing human neocortex, ARHGAP11B is preferentially expressed in neural progenitor cells (NPCs) [6-9]
.
Current research shows that ARHGAP11B is a highly potential candidate gene for neocortical expansion in human evolution
.
Because whether the gene is overexpressed in the neocortex of fetal mice and ferrets, or the gene is expressed at physiological levels in the neocortex of non-human primates (marmosets), the results indicate that it will increase BP.
Proliferation and abundance, which in turn promotes the specific generation of upper neurons, and strengthens the expansion of the developing neocortex [6, 10]
.
However, regarding the potential role of ARHGAP11B in the evolution and expansion of the human neocortex, two key questions remain unanswered: Can the phenotype of ARHGAP11B-induced increase in cortical neurons and expansion of the human neocortex continue into adulthood? If so, is it related to the improvement of cognitive ability? Recently, the Wieland Huttner team of the Max Planck Institute of Molecular Cell Biology and Genetics in Germany published the latest research results in The EMBO Journal entitled Expression of human-specific ARHGAP11B in mice leads to neocortex expansion and increased memory flexibility , Which explains these scientific issues
.
The study found that ARHGAP11B induced the expansion of mouse cortex and the increase of neurons can continue into adulthood, and significantly improved the memory ability of mice
.
The author used CRISPR/Cas9 genome editing technology to transform an allele of mouse Arhgap11a gene into mutant mouse ARHGAP11B gene (mARHGAP11B), thereby obtaining ARHGAP11B transgenic heterozygous mice (hereinafter referred to as 11B mice)
.
Immediately afterwards, the researchers first detected the level of NPC in the developing neocortex of 11B mice and found that 11B mice with a gestational age of 14.
5 days (E14.
5) compared with wild-type (WT) mice of the same age The number of mitotic BPs in the neocortex of the embryo increased by 50%.
These BPs include basal radial glial cells, basal intermediate progenitor cells, etc.
(Figure 1A-K)
.
In order to determine whether the increase in BP levels in the neocortex of 11B mouse embryos is related to the enhancement of cell cycle re-entry, the researchers used injections of thymine analogs to label them.
First, at E13.
5, BrdU was injected for 23.
5 hours and then EdU.
At E14.
5, it was found that BPs in the subventricular zone (SVZ) of 11B mouse embryos were increasingly producing new offspring (Figure 1 L, M), that is to say, BPs may have re-entered the cell cycle , And self-proliferate
.
Second, the number of daughter cells in the ventricular zone (VZ) that are both positive for BrdU and EdU markers, there is no difference between WT and 11B mice, indicating that the self-renewal of apical progenitors (APs) has not changed.
However, there was a significant increase in daughter cells double-positive for this marker in the SVZ of 11B mouse embryos (Figure 1N), indicating an increase in the self-renewal of BPs
.
These results collectively indicate that the proliferation capacity and abundance of BPs in the neocortex of 11B mouse embryos are increased, and this increase is caused by the up-regulation of the ARHGAP11B protein level (down-regulation of the non-allelic Arhgap11a protein level)
.
Figure 1 The proliferation and abundance of BPs in the neocortex of 11B mouse embryos (picture quoted from: Lei Xing, et al.
, EMBO J 2021; 40: e107093) Prove the proliferation and abundance of BPs in the neocortex of 11B mouse embryos After the increase, the authors found that the neocortex of the 11B mouse embryo expanded at E18.
5, and the number of cortical neurons increased (Figure 2A)
.
At the same time, compared with WT embryos, the outer perimeter (Figure 2E) and radial thickness (Figure 2F) of the neocortex of 11B mouse embryos both increased, but the length of the ventricles (Figure 2G) did not increase
.
The increase in radial thickness is due to the increase in the thickness of the cortical plate (CP) and intermediate zone (IZ) of the cortex (Figure 2 H, I).
The increase in radial thickness also reflects the 11B at E18.
5 The increase in the number of neurons in the mouse neocortex (Figure 2 JL)
.
These results prove that in the developing 11B mouse neocortex, the cortex is more expanded and neuron production is more increased
.
Figure 2 Neocortex expansion and increased cortical neuron generation at E18.
5 of 11B mouse embryo (picture quoted from: Lei Xing, et al.
, EMBO J 2021; 40: e107093) Subsequently, the author further studied the 11B mouse From the embryonic stage to the adult stage
.
First, the width and area of the neocortex of 11B mouse P56 (that is, the 56th day after birth) increased significantly (Figure 3 AC)
.
Secondly, the increase in cortical thickness and cortical circumference during embryonic stage of 11B mice can continue into adulthood (Figure 3 E, F)
.
Among them, the increase in CP thickness is the most obvious (Figure 3 GI), and the increase in CP thickness is caused by the special thickening of the epithelial layer (ie II+III layer) (Figure 3 J)
.
Consistent with this, the cerebral cortex of adult 11 B mice showed an increase in the upper neurons of Satb2+ and Brn2+ at P56 (Figure 3 G, H, K, L), while the deep neurons of Ctip2+ did not change (Figure 3 G, M)
.
These results prove that the expansion of the neocortex and the number of upper neurons in 11B mice continue to adulthood.
The difference in the size of the neocortex and the number of upper neurons in adult WT and 11B mice may originate from the embryonic stage of WT and 11B mice.
Different brain development
.
Figure 3 The neocortex continues to expand and the number of cortical neurons increases when the adult 11B mouse brain P56 (picture quoted from: Lei Xing, et al.
, EMBO J 2021; 40: e107093) Next, in order to further explore the effects of ARHGAP11B on mouse nerves The author carried out a series of behavioral tests on the influence of behavior
.
First, for different aspects of learning and memory, they conducted four independent behavioral tests: working memory (Y maze), spatial learning and memory (Barnes maze), associative memory (situational fear conditioning) and memory flexibility (IntelliCage)
.
The first three test results indicate a difference between adult WT and 11B mice
.
However, this does not rule out the influence of the hippocampus on behavior change
.
There was no difference in the abundance of NPCs, the number of newborn neurons, and the protein level of ARHGAP11B in the hippocampus of WT and 11B mice
.
In contrast, IntelliCage is a fully automated behavior evaluation system for evaluating the behavior of mice living in social groups.
The system is used to study the cognitive function of 11B mice, especially long-term learning behavior.
This assessment strictly depends on the function of the neocortex rather than the hippocampus
.
The error recognition rate is used as an indicator of the initial correct position learning and the wrong (that is, reverse) position learning, and is used to evaluate the flexibility of memory
.
The author found that in the initial training stage, both WT and 11B mice can find the correct drinking position, and there is no significant difference between the two (Figure 4 A, B), but in the reverse direction test, it was found that 11B mice could Learn to reverse the rules faster, and the false recognition rate of both males and females is significantly lower than that of WT (Figure 4 C, D)
.
These results indicate that the neocortex-dependent cognitive ability of 11B adult mice is significantly improved, and the adult 11B mice show higher neurobehavioral memory flexibility
.
In addition, the authors also observed that the anxiety level of adult 11B mice was also reduced
.
Figure 4 Improved memory flexibility in 11B mice (picture quoted from: Lei Xing, et al.
, EMBO J 2021; 40: e107093) Conclusion and discussion, inspiration and outlook This study not only confirms the previous research results, but also shows The human-specific gene ARHGAP11B promotes the proliferation of basal progenitor cells (BPs) and the expansion of neocortex during development, and further provides a vital evidence that ARHGAP11B induces an increase in the size of the neocortex and the number of cortical neurons Of adult mice show higher cognitive abilities
.
However, there is no mechanism explanation for how ARHGAP11B induces the expansion of the cortex and the increase of neurons in the upper layer at the molecular level
.
Original link: https:// Selected articles from previous issues [1] Cell Death Differ︱ Qi Yitao/Wu Hongmei and others cooperate to reveal that SUMO chemical modification regulates neurogenesis in adult mice Molecular mechanism [2] Cereb Cortex︱A2A receptor antagonist can reverse the sequence learning impairment induced by abnormal aggregation of α-Syn [3] The new discovery that Neuron︱ nicotine promotes anxiety—inhibition of ventral tegmental area-amygdala dopamine The important role of the pathway [4] Int J Mol Sci︱ Frontier review and interpretation: Pathophysiological response and role of astrocytes in traumatic brain injury [5] Cereb Cortex | Wang Lang's research group reveals that astrocytes are experience-dependent Steady state plasticity [6] Nature︱ new discovery! The social communication of maternal behavior caused by oxytocin neurons [7] Genome Biol︱ Ding Junjun’s team systematically draws a three-dimensional structure map of chromatin during the phase separation, dissolution and reconstruction process [8] New Brain︱ method! Plasma astrocyte proliferation GFAP or a new potential marker for Alzheimer’s disease detection [9] Autophagy︱ Zhang Zhidong’s team reveals a new mechanism for STING1 to induce autophagy to regulate RNA virus infection [10] Nature︱ Astrocytes Source IL-3 regulates the function of microglia, relieves AD pathological changes and cognitive impairment [11] JCI︱ Gao Tianming's research group reveals that the prefrontal cortex has an opposite role in regulating anxiety and fear neural circuits [12] eLife︱ Single-cell sequencing and neural circuit analysis jointly reveal the molecular genetic coding mechanism of brain initiation of attack/defense instinct [13] Nature︱Frontier! GluDs transduce different presynaptic signals to different postsynaptic receptor responses.
References (Swipe up and down to view) 【1】DH Geschwind, P.
Rakic, Cortical evolution: judge the brain by its cover.
Neuron 80, 633-647 (2013).
【2】E.
Ko et al.
,
.
Many genes are related to the expansion of the neocortex, because they have been shown to increase the proliferation and abundance of basal progenitor (BP) cells, thereby promoting the production of cortical neurons [5-9]
.
Among them, ARHGAP11B is a gene unique to humans
.
In the developing human neocortex, ARHGAP11B is preferentially expressed in neural progenitor cells (NPCs) [6-9]
.
Current research shows that ARHGAP11B is a highly potential candidate gene for neocortical expansion in human evolution
.
Because whether the gene is overexpressed in the neocortex of fetal mice and ferrets, or the gene is expressed at physiological levels in the neocortex of non-human primates (marmosets), the results indicate that it will increase BP.
Proliferation and abundance, which in turn promotes the specific generation of upper neurons, and strengthens the expansion of the developing neocortex [6, 10]
.
However, regarding the potential role of ARHGAP11B in the evolution and expansion of the human neocortex, two key questions remain unanswered: Can the phenotype of ARHGAP11B-induced increase in cortical neurons and expansion of the human neocortex continue into adulthood? If so, is it related to the improvement of cognitive ability? Recently, the Wieland Huttner team of the Max Planck Institute of Molecular Cell Biology and Genetics in Germany published the latest research results in The EMBO Journal entitled Expression of human-specific ARHGAP11B in mice leads to neocortex expansion and increased memory flexibility , Which explains these scientific issues
.
The study found that ARHGAP11B induced the expansion of mouse cortex and the increase of neurons can continue into adulthood, and significantly improved the memory ability of mice
.
The author used CRISPR/Cas9 genome editing technology to transform an allele of mouse Arhgap11a gene into mutant mouse ARHGAP11B gene (mARHGAP11B), thereby obtaining ARHGAP11B transgenic heterozygous mice (hereinafter referred to as 11B mice)
.
Immediately afterwards, the researchers first detected the level of NPC in the developing neocortex of 11B mice and found that 11B mice with a gestational age of 14.
5 days (E14.
5) compared with wild-type (WT) mice of the same age The number of mitotic BPs in the neocortex of the embryo increased by 50%.
These BPs include basal radial glial cells, basal intermediate progenitor cells, etc.
(Figure 1A-K)
.
In order to determine whether the increase in BP levels in the neocortex of 11B mouse embryos is related to the enhancement of cell cycle re-entry, the researchers used injections of thymine analogs to label them.
First, at E13.
5, BrdU was injected for 23.
5 hours and then EdU.
At E14.
5, it was found that BPs in the subventricular zone (SVZ) of 11B mouse embryos were increasingly producing new offspring (Figure 1 L, M), that is to say, BPs may have re-entered the cell cycle , And self-proliferate
.
Second, the number of daughter cells in the ventricular zone (VZ) that are both positive for BrdU and EdU markers, there is no difference between WT and 11B mice, indicating that the self-renewal of apical progenitors (APs) has not changed.
However, there was a significant increase in daughter cells double-positive for this marker in the SVZ of 11B mouse embryos (Figure 1N), indicating an increase in the self-renewal of BPs
.
These results collectively indicate that the proliferation capacity and abundance of BPs in the neocortex of 11B mouse embryos are increased, and this increase is caused by the up-regulation of the ARHGAP11B protein level (down-regulation of the non-allelic Arhgap11a protein level)
.
Figure 1 The proliferation and abundance of BPs in the neocortex of 11B mouse embryos (picture quoted from: Lei Xing, et al.
, EMBO J 2021; 40: e107093) Prove the proliferation and abundance of BPs in the neocortex of 11B mouse embryos After the increase, the authors found that the neocortex of the 11B mouse embryo expanded at E18.
5, and the number of cortical neurons increased (Figure 2A)
.
At the same time, compared with WT embryos, the outer perimeter (Figure 2E) and radial thickness (Figure 2F) of the neocortex of 11B mouse embryos both increased, but the length of the ventricles (Figure 2G) did not increase
.
The increase in radial thickness is due to the increase in the thickness of the cortical plate (CP) and intermediate zone (IZ) of the cortex (Figure 2 H, I).
The increase in radial thickness also reflects the 11B at E18.
5 The increase in the number of neurons in the mouse neocortex (Figure 2 JL)
.
These results prove that in the developing 11B mouse neocortex, the cortex is more expanded and neuron production is more increased
.
Figure 2 Neocortex expansion and increased cortical neuron generation at E18.
5 of 11B mouse embryo (picture quoted from: Lei Xing, et al.
, EMBO J 2021; 40: e107093) Subsequently, the author further studied the 11B mouse From the embryonic stage to the adult stage
.
First, the width and area of the neocortex of 11B mouse P56 (that is, the 56th day after birth) increased significantly (Figure 3 AC)
.
Secondly, the increase in cortical thickness and cortical circumference during embryonic stage of 11B mice can continue into adulthood (Figure 3 E, F)
.
Among them, the increase in CP thickness is the most obvious (Figure 3 GI), and the increase in CP thickness is caused by the special thickening of the epithelial layer (ie II+III layer) (Figure 3 J)
.
Consistent with this, the cerebral cortex of adult 11 B mice showed an increase in the upper neurons of Satb2+ and Brn2+ at P56 (Figure 3 G, H, K, L), while the deep neurons of Ctip2+ did not change (Figure 3 G, M)
.
These results prove that the expansion of the neocortex and the number of upper neurons in 11B mice continue to adulthood.
The difference in the size of the neocortex and the number of upper neurons in adult WT and 11B mice may originate from the embryonic stage of WT and 11B mice.
Different brain development
.
Figure 3 The neocortex continues to expand and the number of cortical neurons increases when the adult 11B mouse brain P56 (picture quoted from: Lei Xing, et al.
, EMBO J 2021; 40: e107093) Next, in order to further explore the effects of ARHGAP11B on mouse nerves The author carried out a series of behavioral tests on the influence of behavior
.
First, for different aspects of learning and memory, they conducted four independent behavioral tests: working memory (Y maze), spatial learning and memory (Barnes maze), associative memory (situational fear conditioning) and memory flexibility (IntelliCage)
.
The first three test results indicate a difference between adult WT and 11B mice
.
However, this does not rule out the influence of the hippocampus on behavior change
.
There was no difference in the abundance of NPCs, the number of newborn neurons, and the protein level of ARHGAP11B in the hippocampus of WT and 11B mice
.
In contrast, IntelliCage is a fully automated behavior evaluation system for evaluating the behavior of mice living in social groups.
The system is used to study the cognitive function of 11B mice, especially long-term learning behavior.
This assessment strictly depends on the function of the neocortex rather than the hippocampus
.
The error recognition rate is used as an indicator of the initial correct position learning and the wrong (that is, reverse) position learning, and is used to evaluate the flexibility of memory
.
The author found that in the initial training stage, both WT and 11B mice can find the correct drinking position, and there is no significant difference between the two (Figure 4 A, B), but in the reverse direction test, it was found that 11B mice could Learn to reverse the rules faster, and the false recognition rate of both males and females is significantly lower than that of WT (Figure 4 C, D)
.
These results indicate that the neocortex-dependent cognitive ability of 11B adult mice is significantly improved, and the adult 11B mice show higher neurobehavioral memory flexibility
.
In addition, the authors also observed that the anxiety level of adult 11B mice was also reduced
.
Figure 4 Improved memory flexibility in 11B mice (picture quoted from: Lei Xing, et al.
, EMBO J 2021; 40: e107093) Conclusion and discussion, inspiration and outlook This study not only confirms the previous research results, but also shows The human-specific gene ARHGAP11B promotes the proliferation of basal progenitor cells (BPs) and the expansion of neocortex during development, and further provides a vital evidence that ARHGAP11B induces an increase in the size of the neocortex and the number of cortical neurons Of adult mice show higher cognitive abilities
.
However, there is no mechanism explanation for how ARHGAP11B induces the expansion of the cortex and the increase of neurons in the upper layer at the molecular level
.
Original link: https:// Selected articles from previous issues [1] Cell Death Differ︱ Qi Yitao/Wu Hongmei and others cooperate to reveal that SUMO chemical modification regulates neurogenesis in adult mice Molecular mechanism [2] Cereb Cortex︱A2A receptor antagonist can reverse the sequence learning impairment induced by abnormal aggregation of α-Syn [3] The new discovery that Neuron︱ nicotine promotes anxiety—inhibition of ventral tegmental area-amygdala dopamine The important role of the pathway [4] Int J Mol Sci︱ Frontier review and interpretation: Pathophysiological response and role of astrocytes in traumatic brain injury [5] Cereb Cortex | Wang Lang's research group reveals that astrocytes are experience-dependent Steady state plasticity [6] Nature︱ new discovery! The social communication of maternal behavior caused by oxytocin neurons [7] Genome Biol︱ Ding Junjun’s team systematically draws a three-dimensional structure map of chromatin during the phase separation, dissolution and reconstruction process [8] New Brain︱ method! Plasma astrocyte proliferation GFAP or a new potential marker for Alzheimer’s disease detection [9] Autophagy︱ Zhang Zhidong’s team reveals a new mechanism for STING1 to induce autophagy to regulate RNA virus infection [10] Nature︱ Astrocytes Source IL-3 regulates the function of microglia, relieves AD pathological changes and cognitive impairment [11] JCI︱ Gao Tianming's research group reveals that the prefrontal cortex has an opposite role in regulating anxiety and fear neural circuits [12] eLife︱ Single-cell sequencing and neural circuit analysis jointly reveal the molecular genetic coding mechanism of brain initiation of attack/defense instinct [13] Nature︱Frontier! GluDs transduce different presynaptic signals to different postsynaptic receptor responses.
References (Swipe up and down to view) 【1】DH Geschwind, P.
Rakic, Cortical evolution: judge the brain by its cover.
Neuron 80, 633-647 (2013).
【2】E.
Ko et al.
,
