Dev Cell: Guo Weixiang's team revealed the heterogeneity of origin and function of adult neural stem cells.
Release Date:2023-08-22

Source: BioArt

Adult neural stem cells (neural stem cells, NSCs) in mammals can produce new neurons continuously through a series of processes of proliferation, differentiation and migration, which is called adult neurogenesis. New neurons produced by adult neurogenesis play an important role in learning and memory and emotion regulation, and their functional abnormalities are usually related to various brain diseases.[1].

Adult NSCs is not homogeneous, but shows a high degree of heterogeneity in cell morphology, proliferation, cell potential and function [2-4].However, it is not clear when the heterogeneity of adult NSCs was established and the differences in self-renewal and differentiation ability of different adult NSCs subpopulations in neurogenic niche [5]. Therefore, explaining the origin of different subsets of adult NSCs and their contribution to neurogenesis is a challenging but critical step to promote our understanding of adult NSCs and adult neurogenesis.

During embryonic neural development, morphogenetic factors Wnt (wingless/integrated) and Shh (sonic hedgehog) are distributed in a concentration gradient, which determines the development of the dorsal ventral axis of the brain. Moreover, studies have shown that the regional specificity of adult NSC in the subventricular zone (subventricular zone, SVZ) is determined by the regulation of morphogenetic factors and transcription factors in the early stage of embryonic development. The specific concentration gradients of Wnt and Shh in space and time play an important role in the modeling of embryonic and adult brains, but whether they determine the origin of different adult NSCs subsets is still unknown.

On August 21, 2023, Guo Weixiang's research group from the Institute of Genetics and Developmental Biology of the Chinese Academy of Sciences published a research paper entitled Functional Heterogeneity of Wnt-Responsive and Hedgehog-Responsive Neural Stem Cells in the Murine Adult Hippocampus online in the journal Developmental Cell. This paper not only reveals the multiple origins of heterogeneity of adult NSCs, but also puts forward the concept of functional heterogeneity in different adult NSCs subsets.

IMG_256

The authors used Axin2-CreERT2 or Gli1-CreERT2 mice to track and analyze two different NSCs subsets of Wnt response (Axin2+) and Shh response (Gli1+) in the hippocampus. It was found that the neural progenitors of Axin2+ and Gli1+ contributed adult NSCs in the hippocampus in the early and late stages of embryonic development, respectively. Compared with Gli1+ NSCs,Axin2+ NSCs, it is located in the subgranular layer (subgranular zone) of the hippocampus earlier after birth.

Further studies found that Axin2+ embryonic NSCs transformed into more static adult NSCs in postnatal P3-P5, while Gli1+ embryonic NSCs transformed into more quiescent adult NSCs after birth. These results show that the spatio-temporal origin of Axin2+ and Gli1+ NSCs in adult hippocampus is different.

In order to explore whether there is a difference in the contribution of Axin2+ and Gli1+ NSCs in adult hippocampal neurogenesis, the authors carried out cell clone analysis in vivo. It was found that Axin2+ NSCs had higher proliferative activity and positive self-renewal ability in adult hippocampus, while Gli1+ NSCs was relatively static. At the same time, Axin2+ NSCs was insensitive to environmental stimuli and maintained relatively stable proliferative activity in the aging process, while Gli1+ NSCs had a significant response to environmental stimuli and gradually quieted down with the aging process. This indicates that the contribution of Axin2+ and Gli1+ NSCs to adult neurogenesis in adult hippocampus is different.

In order to find potential molecular and cellular evidence to explain the difference between Axin2+ and Gli1+ NSCs in adult hippocampal neurogenesis, the authors performed scRNA-seq analysis. They found that Axin2+ and Gli1+ NSCs follow different neurogenetic trajectories during hippocampal adult neurogenesis. Further analysis of the morphology of newborn neurons showed that the new neurons produced by Gli1+ NSCs had more complex dendritic branches than those produced by Axin2+ NSCs.

More importantly, through retroviral tracing, it was found that the newborn neurons produced by Gli1+ NSCs showed higher synaptic connection rates than those produced by Axin2+ NSCs, and received more synaptic inputs from different specific brain regions of the brain, such as the medial septum and the entorhinal cortex. These results suggest that there is a certain functional heterogeneity in the neurons differentiated by Axin2+ and Gli1+ NSCs.

In order to explore whether adult Axin2+ and Gli1+ NSCs are involved in different functions of the hippocampus, the authors made floxed-stop manipulate the expressed cytotoxin-diphtheria toxin A subunit (diphtheria toxin subunit A), specifically scavenging Axin2+ and Gli1+ NSCs. Through behavioral analysis, it was found that specific removal of Axin2+ and Gli1+ NSCs could lead to impairment of hippocampal dependent learning and memory, which indicated that Axin2+ and Gli1+ NSCs were necessary for learning and memory. Unexpectedly, only when Axin2+ NSCs was specifically cleared, the mice were more likely to acquire depression-like behavior under restraint stress. This shows that Axin2+ NSCs, rather than Gli1+ NSCs, is directly involved in buffering stress response.

To sum up, through the comprehensive study of embryonic origin, cell proliferation and differentiation and hippocampal function of the above two groups of adult hippocampal NSCs, this study not only reveals the multiple origins of adult NSC heterogeneity, but also further expands the concept of adult NSC heterogeneity: different adult NSC subsets may have different functions and produce neurons with heterogeneity.

Luo Xing, Ph.D. of Guo Weixiang Research Group, Institute of Genetics and Development, Chinese Academy of Sciences, is the first author of this article, and researcher Guo Weixiang is the correspondent author of this article.

Wang Xiujie and Dr. Dai Min, researchers of the Institute of Genetics and Development of the Chinese Academy of Sciences, participated in the study.


IMG_257

Original link:https://10.1016/j.devcel.2023.07.021

Reference

1.Ming, G. L. & Song, H. Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70, 687-702 (2011). https://doi.org:10.1016/j.neuron.2011.05.001 

2.Bonaguidi, M. A. et al. Diversity of Neural Precursors in the Adult Mammalian Brain. Cold Spring Harb Perspect Biol 8, a018838 (2016). https://doi.org:10.1101/cshperspect.a018838 

3.Goodell, M. A., Nguyen, H. & Shroyer, N. Somatic stem cell heterogeneity: diversity in the blood, skin and intestinal stem cell compartments. Nat Rev Mol Cell Bio 16, 299-309 (2015). https://doi.org:10.1038/nrm3980 

4.Donati, G. & Watt, F. M. Stem cell heterogeneity and plasticity in epithelia. Cell Stem Cell 16, 465-476 (2015). https://doi.org:10.1016/j.stem.2015.04.014 

5.Berg, D. A., Bond, A. M., Ming, G. L. & Song, H. Radial glial cells in the adult dentate gyrus: what are they and where do they come from? F1000Res 7, 277 (2018). https://doi.org:10.12688/f1000research.12684.1

Return to List
Prve:Cell sub-journal: organ-like study reveals metabolic typing of pancreatic cancer and discovers new therapeutic targets
Next:National Science Review: Gao Shaorong / Liu Wenqiang / Gao Shuai unveils the "black box" of abnormal development of somatic cloned embryos during peri-implantation.