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And explore the mysteries of neuroscience with rigorous academic and logical thinking︱Shi Xiang, Zhang Yuhong in charge of writing︱Wang Sizhen The nervous system is one of the most complex and important organs of the human body.
A deep understanding of neurodevelopment plays an important role in neuroscience research and regenerative medicine.
【1】.
To study neural development, it is necessary to systematically understand the types, characteristics, lineage fate of neural precursor cells, and the differentiation and maturation process of neurons.
In the past few decades, a large number of research results have gradually revealed the neurogenesis mechanism and lineage development rules of mammalian laminar structures (cerebral cortex and retina) [2-4].
Interestingly, the fate of neural precursor cells in the cerebral cortex is often pre-determined in the process of differentiation into neurons, which we call the "fate determination model" [2]; retinal precursor cells can randomly generate different changes during the differentiation process.
This type of neuron is called "random decision model" [3].
However, the hypothalamus, as a highly complex brain region that is essential for life maintenance, the complex cell lineage evolution during its development and the origin of neuronal diversity are still an unsolved problem.
On April 21, 2021, the research results of Wu Qingfeng's research group from the Institute of Genetics and Developmental Biology of the Chinese Academy of Sciences titled "Cascade diversification directs generation of neuronal diversity in the hypothalamus" online in Cell Stem Cell.
The study combined lineage tracking and single-cell transcriptome sequencing technology to draw a blueprint for the dynamic development of the mouse hypothalamus and analyze the origin of the neuronal diversity of the mouse hypothalamus.
First, the researchers cleverly used hypothalamic-specific marker mice to perform lineage tracing and flow sorting of hypothalamic cells in the embryonic and early postnatal stages, and then performed single-cell RNA sequencing and data analysis, and a total of 8 were identified.
Main cell types: radial glial cells (RGCs), intermediate precursor cells (IPCs), glutamatergic neurons (GLU), gamma-aminobutyric acid neurons (GABA), astrocytes (AS) , Oligodendrocyte precursor cells (OPC), oligodendrocytes (OD) and ependymal cells (EC) (Figure 1).
Figure 1.
Single-cell map of mouse hypothalamus development (Zhang et al.
, Cell Stem Cell (2021)) Secondly, radioglial cells (RGCs) are the highest level of stem cells in the neurogenesis lineage (2).
The researchers’ analysis of these cells showed that even in the early stages of development, RGCs cells have obvious internal heterogeneity, which can be divided into different precursor cell subtypes according to the cell cycle state and expression profile.
It also showed obvious priming signals before differentiation (Figure 2A-E).
Importantly, the researchers also revealed the next special group of somatic stem cells, namely thalamic extension cells, which, like adult neural stem cells in the lateral ventricle, are reserved at the embryonic stage of brain development, rather than at the end of embryonic development.
Come (Figure 2F-J).
Figure 2.
Strategically conservative RGCs enter a resting state during the embryonic stage to reserve for the formation of stretched cells (Zhang et al.
, Cell Stem Cell (2021)) Third, the researchers found after analyzing the early neuronal developmental lineages , Hypothalamic RGCs produced two clusters of intermediate precursor cells (IPC), which were defined as Ascl1+ and Neurog2+ hypothalamic IPCs (Figure 3A-B). Ascl1 and Neurog2 are two important pro-neural factors in mammals.
Both are transcription factors of the basic helix-loop-helix (bHLH) family.
They play an important role in initiating and regulating neurogenesis.
Past studies have shown that Ascl1 and Neurog2 are in The central nervous system has important fate regulation effects on GABAergic (inhibitory) and glutamatergic (excitatory) neurons, respectively; and they have fate-determining effects on sympathetic and sensory neurons in the peripheral nervous system respectively [5] .
After functional enrichment analysis, immunostaining and population lineage tracking of these two groups of IPC cells, it was found that the IPCs of Ascl1+ and Neurog2+ showed different molecular signals, spatial distribution and developmental potential (Figure 3C-M).
One of the very interesting findings is that, different from the telencephalon, Ascl1+ IPCs can produce both inhibitory neurons and excitatory neurons in the hypothalamus, while Neurog2+ IPCs only produce excitatory neurons (Figure 3E-I).
These results indicate that there are two completely different groups of IPCs in the hypothalamus at the same time, and one group of IPCs can have a significant two-way fate.
Figure 3.
The molecular characteristics, spatial distribution and differentiation potential of two different IPCs in the hypothalamus (Zhang et al.
, Cell Stem Cell (2021)) Next, the study identified 29 types of unique transcription factors, neurotransmitters and nerves.
The peptide combination encodes neuronal subtypes, and analyzes the spatial positioning, developmental maturity, and fate determinant regulatory network of these neuronal subgroups, thereby providing a map of developing hypothalamic neurons (Figure 4).
Figure 4.
Subtype classification, spatial positioning and maturation status of hypothalamic neurons (Zhang et al.
, Cell Stem Cell (2021)) In addition, the study also found that newborn neurons can be further differentiated into diversified peptidergic neurons Yuan, and find three groups of "One Life One", "One Life Two" and "One Life Three" peptidergic neuron development patterns (Figure 5).
This further shows that the neuronal population in the hypothalamus after mitosis has gradually contributed more complex neuronal diversity during the developmental transition from the immature state to the mature state.
Figure 5.
Three representative differentiation patterns of hypothalamic neonatal neurons (Zhang et al.
, Cell Stem Cell (2021)) Finally, the researchers adopted a monoclonal lineage tracking system based on a chimeric two-color marker (MADM) system [6 ] And three-dimensional reconstruction technology analyzed the lineage development of a single Rax+RGC in the mouse hypothalamus, and confirmed and analyzed the clone composition and spatial distribution of the progeny cells (Figure 6).
The immunostaining results further showed that multiple neuron subtypes do have a common origin at the single-cell level, revealing the neuronal diversity produced by a single RGC cell during the development of the hypothalamus (Figure 6).
Figure 6.
The MADM system tracks the proliferative potential of a single RGC in the hypothalamus (Zhang et al.
, Cell Stem Cell (2021)).
In general, this study provides a single-cell level hypothalamic developmental network, indicating a developmental lineage tree The multiple cell types on the cell are advanced and amplified step by step, resulting in neuronal subtypes with diversified fates.
In addition, the study also analyzed the embryonic origin of hypothalamic extension cells and the fate determinants of the regulatory neuronal subtypes, which will help understand the dynamic development process of the hypothalamus and the fate determination of highly diverse neurons, which is anorexia The diagnosis, treatment and prevention of neurological diseases such as drowsiness, sleepiness and insomnia provide important theoretical scientific basis (Figure 7).
Figure 7.
The "cascade diversification" model of neuron development (Zhang et al.
, Cell Stem Cell (2021)) Researcher Wu Qingfeng, Institute of Genetics and Development, Chinese Academy of Sciences, is the corresponding author of this article.
Doctoral students Zhang Yuhong, Xu Mingrui and Shi in Wu Qingfeng's research group Xiang, master student Sun Xuelian and postdoctoral fellow Mu Wenhui are the co-first authors.
Professor Yao Mingze of Shanxi University and Professor He Miao of Fudan University participated in the research.
The research was supported by the National Key Research and Development Program, the National Natural Science Foundation of China, the Strategic Leading Science and Technology Project of the Chinese Academy of Sciences, the Hundred Talents Program of the Chinese Academy of Sciences, and the Technical Committee of the Beijing Academy of Science and Engineering.
Original link: https://doi.
org/10.
1016/j.
stem.
2021.
03.
020 Recommended high-quality scientific research training courses [1] Medicine plus patch clamp and optogenetic and calcium imaging technology seminar (April 24-25, 2 days and 1 night) [2] Online ︱Single Cell Sequencing Data Analysis and Research Thinking Seminar (January 16-17, 21) (courses can be booked from April to May 2021) [3] Multimodal Brain Image data processing analysis/machine learning application online training brain image: 17-18 Machine learning: 23-24 reference (slide up and down to view) [1] PR John LR Rubenstein, Patterning and Cell Type Specification in the Developing CNS and PNS .
(2013).
[2] M.
Kohwi, CQ Doe, Temporal fate specification and neural progenitor competence during development.
Nat Rev Neurosci 14, 823-838 (2013).
[3] J.
He et al.
, How variable clones build an invariant retina.
Neuron 75, 786-798 (2012).
[4] P.
Gao et al.
, Deterministic progenitor behavior and unitary production of neurons in the neocortex.
Cell 159, 775-788 (2014).
[5] B.
Aydin et al.
, Proneural factors Ascl1 and Neurog2 contribute to neuronal subtype identities by establishing distinct chromatin landscapes.
Nat Neurosci 22,897-908 (2019).
[6] H.
Zong, JS Espinosa, HH Su, MD Muzumdar, L.
Luo, Mosaic analysis with double markers in mice.
Cell 121, 479-492 (2005).
A deep understanding of neurodevelopment plays an important role in neuroscience research and regenerative medicine.
【1】.
To study neural development, it is necessary to systematically understand the types, characteristics, lineage fate of neural precursor cells, and the differentiation and maturation process of neurons.
In the past few decades, a large number of research results have gradually revealed the neurogenesis mechanism and lineage development rules of mammalian laminar structures (cerebral cortex and retina) [2-4].
Interestingly, the fate of neural precursor cells in the cerebral cortex is often pre-determined in the process of differentiation into neurons, which we call the "fate determination model" [2]; retinal precursor cells can randomly generate different changes during the differentiation process.
This type of neuron is called "random decision model" [3].
However, the hypothalamus, as a highly complex brain region that is essential for life maintenance, the complex cell lineage evolution during its development and the origin of neuronal diversity are still an unsolved problem.
On April 21, 2021, the research results of Wu Qingfeng's research group from the Institute of Genetics and Developmental Biology of the Chinese Academy of Sciences titled "Cascade diversification directs generation of neuronal diversity in the hypothalamus" online in Cell Stem Cell.
The study combined lineage tracking and single-cell transcriptome sequencing technology to draw a blueprint for the dynamic development of the mouse hypothalamus and analyze the origin of the neuronal diversity of the mouse hypothalamus.
First, the researchers cleverly used hypothalamic-specific marker mice to perform lineage tracing and flow sorting of hypothalamic cells in the embryonic and early postnatal stages, and then performed single-cell RNA sequencing and data analysis, and a total of 8 were identified.
Main cell types: radial glial cells (RGCs), intermediate precursor cells (IPCs), glutamatergic neurons (GLU), gamma-aminobutyric acid neurons (GABA), astrocytes (AS) , Oligodendrocyte precursor cells (OPC), oligodendrocytes (OD) and ependymal cells (EC) (Figure 1).
Figure 1.
Single-cell map of mouse hypothalamus development (Zhang et al.
, Cell Stem Cell (2021)) Secondly, radioglial cells (RGCs) are the highest level of stem cells in the neurogenesis lineage (2).
The researchers’ analysis of these cells showed that even in the early stages of development, RGCs cells have obvious internal heterogeneity, which can be divided into different precursor cell subtypes according to the cell cycle state and expression profile.
It also showed obvious priming signals before differentiation (Figure 2A-E).
Importantly, the researchers also revealed the next special group of somatic stem cells, namely thalamic extension cells, which, like adult neural stem cells in the lateral ventricle, are reserved at the embryonic stage of brain development, rather than at the end of embryonic development.
Come (Figure 2F-J).
Figure 2.
Strategically conservative RGCs enter a resting state during the embryonic stage to reserve for the formation of stretched cells (Zhang et al.
, Cell Stem Cell (2021)) Third, the researchers found after analyzing the early neuronal developmental lineages , Hypothalamic RGCs produced two clusters of intermediate precursor cells (IPC), which were defined as Ascl1+ and Neurog2+ hypothalamic IPCs (Figure 3A-B). Ascl1 and Neurog2 are two important pro-neural factors in mammals.
Both are transcription factors of the basic helix-loop-helix (bHLH) family.
They play an important role in initiating and regulating neurogenesis.
Past studies have shown that Ascl1 and Neurog2 are in The central nervous system has important fate regulation effects on GABAergic (inhibitory) and glutamatergic (excitatory) neurons, respectively; and they have fate-determining effects on sympathetic and sensory neurons in the peripheral nervous system respectively [5] .
After functional enrichment analysis, immunostaining and population lineage tracking of these two groups of IPC cells, it was found that the IPCs of Ascl1+ and Neurog2+ showed different molecular signals, spatial distribution and developmental potential (Figure 3C-M).
One of the very interesting findings is that, different from the telencephalon, Ascl1+ IPCs can produce both inhibitory neurons and excitatory neurons in the hypothalamus, while Neurog2+ IPCs only produce excitatory neurons (Figure 3E-I).
These results indicate that there are two completely different groups of IPCs in the hypothalamus at the same time, and one group of IPCs can have a significant two-way fate.
Figure 3.
The molecular characteristics, spatial distribution and differentiation potential of two different IPCs in the hypothalamus (Zhang et al.
, Cell Stem Cell (2021)) Next, the study identified 29 types of unique transcription factors, neurotransmitters and nerves.
The peptide combination encodes neuronal subtypes, and analyzes the spatial positioning, developmental maturity, and fate determinant regulatory network of these neuronal subgroups, thereby providing a map of developing hypothalamic neurons (Figure 4).
Figure 4.
Subtype classification, spatial positioning and maturation status of hypothalamic neurons (Zhang et al.
, Cell Stem Cell (2021)) In addition, the study also found that newborn neurons can be further differentiated into diversified peptidergic neurons Yuan, and find three groups of "One Life One", "One Life Two" and "One Life Three" peptidergic neuron development patterns (Figure 5).
This further shows that the neuronal population in the hypothalamus after mitosis has gradually contributed more complex neuronal diversity during the developmental transition from the immature state to the mature state.
Figure 5.
Three representative differentiation patterns of hypothalamic neonatal neurons (Zhang et al.
, Cell Stem Cell (2021)) Finally, the researchers adopted a monoclonal lineage tracking system based on a chimeric two-color marker (MADM) system [6 ] And three-dimensional reconstruction technology analyzed the lineage development of a single Rax+RGC in the mouse hypothalamus, and confirmed and analyzed the clone composition and spatial distribution of the progeny cells (Figure 6).
The immunostaining results further showed that multiple neuron subtypes do have a common origin at the single-cell level, revealing the neuronal diversity produced by a single RGC cell during the development of the hypothalamus (Figure 6).
Figure 6.
The MADM system tracks the proliferative potential of a single RGC in the hypothalamus (Zhang et al.
, Cell Stem Cell (2021)).
In general, this study provides a single-cell level hypothalamic developmental network, indicating a developmental lineage tree The multiple cell types on the cell are advanced and amplified step by step, resulting in neuronal subtypes with diversified fates.
In addition, the study also analyzed the embryonic origin of hypothalamic extension cells and the fate determinants of the regulatory neuronal subtypes, which will help understand the dynamic development process of the hypothalamus and the fate determination of highly diverse neurons, which is anorexia The diagnosis, treatment and prevention of neurological diseases such as drowsiness, sleepiness and insomnia provide important theoretical scientific basis (Figure 7).
Figure 7.
The "cascade diversification" model of neuron development (Zhang et al.
, Cell Stem Cell (2021)) Researcher Wu Qingfeng, Institute of Genetics and Development, Chinese Academy of Sciences, is the corresponding author of this article.
Doctoral students Zhang Yuhong, Xu Mingrui and Shi in Wu Qingfeng's research group Xiang, master student Sun Xuelian and postdoctoral fellow Mu Wenhui are the co-first authors.
Professor Yao Mingze of Shanxi University and Professor He Miao of Fudan University participated in the research.
The research was supported by the National Key Research and Development Program, the National Natural Science Foundation of China, the Strategic Leading Science and Technology Project of the Chinese Academy of Sciences, the Hundred Talents Program of the Chinese Academy of Sciences, and the Technical Committee of the Beijing Academy of Science and Engineering.
Original link: https://doi.
org/10.
1016/j.
stem.
2021.
03.
020 Recommended high-quality scientific research training courses [1] Medicine plus patch clamp and optogenetic and calcium imaging technology seminar (April 24-25, 2 days and 1 night) [2] Online ︱Single Cell Sequencing Data Analysis and Research Thinking Seminar (January 16-17, 21) (courses can be booked from April to May 2021) [3] Multimodal Brain Image data processing analysis/machine learning application online training brain image: 17-18 Machine learning: 23-24 reference (slide up and down to view) [1] PR John LR Rubenstein, Patterning and Cell Type Specification in the Developing CNS and PNS .
(2013).
[2] M.
Kohwi, CQ Doe, Temporal fate specification and neural progenitor competence during development.
Nat Rev Neurosci 14, 823-838 (2013).
[3] J.
He et al.
, How variable clones build an invariant retina.
Neuron 75, 786-798 (2012).
[4] P.
Gao et al.
, Deterministic progenitor behavior and unitary production of neurons in the neocortex.
Cell 159, 775-788 (2014).
[5] B.
Aydin et al.
, Proneural factors Ascl1 and Neurog2 contribute to neuronal subtype identities by establishing distinct chromatin landscapes.
Nat Neurosci 22,897-908 (2019).
[6] H.
Zong, JS Espinosa, HH Su, MD Muzumdar, L.
Luo, Mosaic analysis with double markers in mice.
Cell 121, 479-492 (2005).
