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Comments | Zhang Xu (Academician of the Chinese Academy of Sciences), Shi Songhai (Tsinghua University) Editor | The nervous system is one of the most complex and important organs of the human body.
An in-depth understanding of neurodevelopment plays an important role in neuroscience research and regenerative medicine.
Various neurological and mental diseases caused by abnormal brain development have brought heavy psychological and economic burdens to countless families and societies.
Using model animals to clarify the fundamental and key issues in neurodevelopmental biology is an important task of modern life science research.
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).
Interestingly, the fate of neural precursor cells in the cerebral cortex is often pre-determined during the process of differentiation into neurons, which we call the "fate determination model"; during the differentiation process, retinal precursor cells can randomly generate different types of nerves.
Meta, we call it "random decision model".
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, Qingfeng Wu's group from the Institute of Genetics and Development of the Chinese Academy of Sciences published an online paper entitled Cascade Diversification Directs Generation of Neuronal Diversity in the Hypothalamus on Cell Stem Cell.
The study combined lineage tracking and single-cell technology to sequence and analyze the transcriptome of 43,261 developing mouse hypothalamic cells, map the dynamic development trajectory of the mouse hypothalamus, and identify radial glial cells (RGCs) , Intermediate Precursor Cells (IPCs), Newborn Neurons (Nascent Neurons) to Peptidergic Neurons (Peptidergic Neurons) Hypothalamus Developmental Tree, and proposed "cascade amplification law" to explain the neuronal diversity of complex brain regions origin.
The researchers first used the hypothalamic-specific labeling tool mouse to mark the hypothalamic cells at four periods of embryonic day 11 (E11), 14 (E14), postpartum 0 (P0), and 7 (P7).
Flow sorting, single-cell transcriptome data was obtained, and a total of 8 large groups of nerve cells were identified.
Among them, RGC, IPC, newborn neurons and peptidergic neurons are distributed in the four levels of cell lineage from high to low.
RGCs, or embryonic neural stem cells, are at the highest level of the neural cell lineage.
Researchers’ analysis of these cells showed that even in the early stages of development, RGCs cells have already appeared strong heterogeneity, which can be divided into diversified precursor cell subtypes according to the cell cycle state and expression profile.
And showed a specific differentiation initiation signal.
RGCs can differentiate with multiple potentials and produce two groups of IPCs with completely complementary spatial distributions and different molecular expression profiles.
IPCs are neuron precursor cells with the ability to divide.
The two groups of IPCs mentioned above can be labeled with two transcription factors, Ascl1 and Neurog2, respectively.
In the cerebral cortex, glutamatergic (excitatory) and GABAergic (inhibitory) neurons have completely different cellular origins.
Excitingly, the researchers discovered that there is a group of IPCs in the hypothalamus that show bidirectional fate, which can produce glutamatergic and GABAergic neurons at the same time; while another group of IPCs can only produce glutamatergic neurons.
How exactly this shift occurs in brain evolution, that is, the simplification of IPC's fate, is a question worthy of further study.
Newborn neurons are produced by IPC, but they no longer have the ability to divide.
In the process of new neurons, there can be further diversification of fates, and a variety of peptidergic neurons can be produced.
The researchers found three groups of peptidergic neuron maturation patterns, namely "One Life One", "One Life Two" and "One Life Three", which further produced more complex neuronal diversity.
In addition, the research also puts forward several important knowledge points, which expands the research boundary of hypothalamic development.
First, the hypothalamic extension cells, the so-called "third group of adult neural stem cells", are produced by RGCs reserved during embryonic development, and do not form in the later stages of development; second, the researchers identified a The fate determinants of a series of hypothalamic neurons have laid an important foundation for the regeneration of special peptidergic neurons.
Finally, Wu Qingfeng’s team used a chimeric two-color marker (MADM) system to conduct single-cell lineage tracking, that is, clonal analysis, and proved that a single RGC can generate an average of 7.
9 neurons, and they have the ability to differentiate into multiple neuronal subtypes.
.
In short, this study successfully traced the developmental trajectory of RGCs, IPCs, newborn neurons and peptidergic neurons in the hypothalamic neural lineage through lineage tracing technology and single cell analysis, and identified the molecular characteristics and development of key cell groups.
Potential, and finally clarified the source of complexity of hypothalamic neurons, revealing new laws.
Original link: https://doi.
org/10.
1016/j.
stem.
2021.
03.
020 Expert comment Zhang Xu (Academician of Chinese Academy of Sciences, Researcher of Shanghai Institute for Advanced Study, Chinese Academy of Sciences) The hypothalamus is one of the most complex brain regions in the central nervous system , Neurons are highly diverse, capable of secreting diverse neuropeptides and neurotransmitters, and regulating a series of instinctive behaviors and endocrines that are vital to life.
How important is the hypothalamus? It is in charge of many elements that sustain life: eating, drinking, sleeping, and reproduction.
Numerous instinctive behaviors, such as feeding behavior and mating behavior, are complex behaviors that can be observed in animals without any training, and are closely related to the survival and reproduction of individuals.
The control of these complex behaviors is determined by the diversity of neuron types, because the diversity of neurons determines the diversity of related neural circuits that can be established, and in turn determines their behavior.
Although we have studied the anatomy, function and cell classification of these hypothalamus to a certain extent, we still lack understanding of the cell lineage of the hypothalamus, and more importantly, how the complexity of hypothalamic neurons is generated ? These important basic scientific issues are still largely unknown.
This research work by Wu Qingfeng's laboratory has drawn a new dynamic blueprint for the development of hypothalamus, revealing the molecular regulation mechanism of hypothalamic neuronal diversity and the evolution of cell lineage.
Very importantly, the study identified different types of neural precursor cells (RGCs), intermediate precursor cells (IPCs) and neurons of different developmental maturities in the hypothalamus, identified their molecular signature profiles, and analyzed Cell development profile and fate determinants of different neurons.
One of the important findings is to identify two groups of IPCs, one of which can produce excitatory and inhibitory neurons at the same time, and use a series of lineage tracking experiments to propose a cascade amplification model to explain the generation of neuronal diversity.
On the basis of drawing the dynamic developmental trajectory of hypothalamic neurons, this research work has answered in detail the important basic question about the origin of hypothalamic neuronal diversity for the first time.
It is a major breakthrough in the research field of hypothalamic development.
They also identified the molecular characteristics of key cell types and revealed the developmental potential of hypothalamic precursor cells, which will help understand the development process of the dynamic changes of the hypothalamus, as well as a series of complex neurological diseases such as anorexia, lethargy, and insomnia.
The research provided important clues.
Shi Songhai (Professor, School of Life Sciences, Tsinghua University, Dean of Tsinghua-IDG/McGovern Institute for Brain Science) Neuronal diversity and its origin have always been one of the core issues of developmental neurobiology.
Hypothalamic neurons form a neural circuit through complex synaptic connections, thereby regulating a series of behaviors such as breastfeeding, drinking, sleep, mood, and circadian rhythm.
However, the origin and diversity of nerve cells in the hypothalamus has not been well resolved.
In previous studies, it is difficult to accurately track the lineage progress of hypothalamic neural precursor cells and the differentiation and maturation of neurons because there is no effective technical means to isolate or label effective hypothalamic tissues or cells in the early stage of embryonic development.
process.
In an article from Wu Qingfeng’s research team published in this issue of Cell Stem Cell, the researchers used specifically labeled tool mice to perform in-body lineage tracking and single-cell transcriptome analysis of the hypothalamus, which not only overcomes manual microdissection sampling Due to the limitation, it also captured a large number of radial glial cells and intermediate precursor cells in the early stage of hypothalamic neurogenesis.
In addition, this study uses Mosaic analysis with double markers (MADM) to perform temporal and spatial-specific in vivo fluorescent labeling of single neural stem cells, so as to quantitatively analyze radial glial cells (Radial glial cells) at the single-cell level.
glial cells (RGCs) split to produce the behavior of neurons and glial cells, revealing the types, numbers, and distribution characteristics of offspring nerve cells, providing unprecedented resolution for studying the diverse magnification modes of hypothalamic neural stem cells at the single-cell level .
This study by Wu Qingfeng's team has precisely clarified the early neurogenesis pattern of the hypothalamus for the first time and answered the question of the origin of neuronal complication.
This will greatly promote the forward development of the field of hypothalamic science, and at the same time promote the further deepening and expansion of related neuroscience fields.
Qingfeng Wu's research group recruits postdoctoral fellows from the Institute of Genetics and Development, Chinese Academy of Sciences.
Qingfeng Wu's research group is mainly engaged in neurodevelopment and neuroregulation and metabolism.
Related research has been published in journals such as Cell, Cell Stem Cell, Nat Commun, Cell Reports and PLoS Bio.
The research group is now openly recruiting 1-2 post-doctoral researchers engaged in developmental biology, neurobiology, and bioinformatics.
Salaries and benefits are competitive. Resume delivery (if you are interested, you can send your resume and relevant supporting materials to): https://jinshuju.
net/f/ZqXwZt or scan the QR code to post your resume.
Plate maker: 11 reprint instructions [Non-original article] The copyright of this article belongs to The article is owned by the author, personal forwarding and sharing are welcome, reprinting is prohibited without permission, the author has all legal rights, and offenders must be investigated.
An in-depth understanding of neurodevelopment plays an important role in neuroscience research and regenerative medicine.
Various neurological and mental diseases caused by abnormal brain development have brought heavy psychological and economic burdens to countless families and societies.
Using model animals to clarify the fundamental and key issues in neurodevelopmental biology is an important task of modern life science research.
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).
Interestingly, the fate of neural precursor cells in the cerebral cortex is often pre-determined during the process of differentiation into neurons, which we call the "fate determination model"; during the differentiation process, retinal precursor cells can randomly generate different types of nerves.
Meta, we call it "random decision model".
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, Qingfeng Wu's group from the Institute of Genetics and Development of the Chinese Academy of Sciences published an online paper entitled Cascade Diversification Directs Generation of Neuronal Diversity in the Hypothalamus on Cell Stem Cell.
The study combined lineage tracking and single-cell technology to sequence and analyze the transcriptome of 43,261 developing mouse hypothalamic cells, map the dynamic development trajectory of the mouse hypothalamus, and identify radial glial cells (RGCs) , Intermediate Precursor Cells (IPCs), Newborn Neurons (Nascent Neurons) to Peptidergic Neurons (Peptidergic Neurons) Hypothalamus Developmental Tree, and proposed "cascade amplification law" to explain the neuronal diversity of complex brain regions origin.
The researchers first used the hypothalamic-specific labeling tool mouse to mark the hypothalamic cells at four periods of embryonic day 11 (E11), 14 (E14), postpartum 0 (P0), and 7 (P7).
Flow sorting, single-cell transcriptome data was obtained, and a total of 8 large groups of nerve cells were identified.
Among them, RGC, IPC, newborn neurons and peptidergic neurons are distributed in the four levels of cell lineage from high to low.
RGCs, or embryonic neural stem cells, are at the highest level of the neural cell lineage.
Researchers’ analysis of these cells showed that even in the early stages of development, RGCs cells have already appeared strong heterogeneity, which can be divided into diversified precursor cell subtypes according to the cell cycle state and expression profile.
And showed a specific differentiation initiation signal.
RGCs can differentiate with multiple potentials and produce two groups of IPCs with completely complementary spatial distributions and different molecular expression profiles.
IPCs are neuron precursor cells with the ability to divide.
The two groups of IPCs mentioned above can be labeled with two transcription factors, Ascl1 and Neurog2, respectively.
In the cerebral cortex, glutamatergic (excitatory) and GABAergic (inhibitory) neurons have completely different cellular origins.
Excitingly, the researchers discovered that there is a group of IPCs in the hypothalamus that show bidirectional fate, which can produce glutamatergic and GABAergic neurons at the same time; while another group of IPCs can only produce glutamatergic neurons.
How exactly this shift occurs in brain evolution, that is, the simplification of IPC's fate, is a question worthy of further study.
Newborn neurons are produced by IPC, but they no longer have the ability to divide.
In the process of new neurons, there can be further diversification of fates, and a variety of peptidergic neurons can be produced.
The researchers found three groups of peptidergic neuron maturation patterns, namely "One Life One", "One Life Two" and "One Life Three", which further produced more complex neuronal diversity.
In addition, the research also puts forward several important knowledge points, which expands the research boundary of hypothalamic development.
First, the hypothalamic extension cells, the so-called "third group of adult neural stem cells", are produced by RGCs reserved during embryonic development, and do not form in the later stages of development; second, the researchers identified a The fate determinants of a series of hypothalamic neurons have laid an important foundation for the regeneration of special peptidergic neurons.
Finally, Wu Qingfeng’s team used a chimeric two-color marker (MADM) system to conduct single-cell lineage tracking, that is, clonal analysis, and proved that a single RGC can generate an average of 7.
9 neurons, and they have the ability to differentiate into multiple neuronal subtypes.
.
In short, this study successfully traced the developmental trajectory of RGCs, IPCs, newborn neurons and peptidergic neurons in the hypothalamic neural lineage through lineage tracing technology and single cell analysis, and identified the molecular characteristics and development of key cell groups.
Potential, and finally clarified the source of complexity of hypothalamic neurons, revealing new laws.
Original link: https://doi.
org/10.
1016/j.
stem.
2021.
03.
020 Expert comment Zhang Xu (Academician of Chinese Academy of Sciences, Researcher of Shanghai Institute for Advanced Study, Chinese Academy of Sciences) The hypothalamus is one of the most complex brain regions in the central nervous system , Neurons are highly diverse, capable of secreting diverse neuropeptides and neurotransmitters, and regulating a series of instinctive behaviors and endocrines that are vital to life.
How important is the hypothalamus? It is in charge of many elements that sustain life: eating, drinking, sleeping, and reproduction.
Numerous instinctive behaviors, such as feeding behavior and mating behavior, are complex behaviors that can be observed in animals without any training, and are closely related to the survival and reproduction of individuals.
The control of these complex behaviors is determined by the diversity of neuron types, because the diversity of neurons determines the diversity of related neural circuits that can be established, and in turn determines their behavior.
Although we have studied the anatomy, function and cell classification of these hypothalamus to a certain extent, we still lack understanding of the cell lineage of the hypothalamus, and more importantly, how the complexity of hypothalamic neurons is generated ? These important basic scientific issues are still largely unknown.
This research work by Wu Qingfeng's laboratory has drawn a new dynamic blueprint for the development of hypothalamus, revealing the molecular regulation mechanism of hypothalamic neuronal diversity and the evolution of cell lineage.
Very importantly, the study identified different types of neural precursor cells (RGCs), intermediate precursor cells (IPCs) and neurons of different developmental maturities in the hypothalamus, identified their molecular signature profiles, and analyzed Cell development profile and fate determinants of different neurons.
One of the important findings is to identify two groups of IPCs, one of which can produce excitatory and inhibitory neurons at the same time, and use a series of lineage tracking experiments to propose a cascade amplification model to explain the generation of neuronal diversity.
On the basis of drawing the dynamic developmental trajectory of hypothalamic neurons, this research work has answered in detail the important basic question about the origin of hypothalamic neuronal diversity for the first time.
It is a major breakthrough in the research field of hypothalamic development.
They also identified the molecular characteristics of key cell types and revealed the developmental potential of hypothalamic precursor cells, which will help understand the development process of the dynamic changes of the hypothalamus, as well as a series of complex neurological diseases such as anorexia, lethargy, and insomnia.
The research provided important clues.
Shi Songhai (Professor, School of Life Sciences, Tsinghua University, Dean of Tsinghua-IDG/McGovern Institute for Brain Science) Neuronal diversity and its origin have always been one of the core issues of developmental neurobiology.
Hypothalamic neurons form a neural circuit through complex synaptic connections, thereby regulating a series of behaviors such as breastfeeding, drinking, sleep, mood, and circadian rhythm.
However, the origin and diversity of nerve cells in the hypothalamus has not been well resolved.
In previous studies, it is difficult to accurately track the lineage progress of hypothalamic neural precursor cells and the differentiation and maturation of neurons because there is no effective technical means to isolate or label effective hypothalamic tissues or cells in the early stage of embryonic development.
process.
In an article from Wu Qingfeng’s research team published in this issue of Cell Stem Cell, the researchers used specifically labeled tool mice to perform in-body lineage tracking and single-cell transcriptome analysis of the hypothalamus, which not only overcomes manual microdissection sampling Due to the limitation, it also captured a large number of radial glial cells and intermediate precursor cells in the early stage of hypothalamic neurogenesis.
In addition, this study uses Mosaic analysis with double markers (MADM) to perform temporal and spatial-specific in vivo fluorescent labeling of single neural stem cells, so as to quantitatively analyze radial glial cells (Radial glial cells) at the single-cell level.
glial cells (RGCs) split to produce the behavior of neurons and glial cells, revealing the types, numbers, and distribution characteristics of offspring nerve cells, providing unprecedented resolution for studying the diverse magnification modes of hypothalamic neural stem cells at the single-cell level .
This study by Wu Qingfeng's team has precisely clarified the early neurogenesis pattern of the hypothalamus for the first time and answered the question of the origin of neuronal complication.
This will greatly promote the forward development of the field of hypothalamic science, and at the same time promote the further deepening and expansion of related neuroscience fields.
Qingfeng Wu's research group recruits postdoctoral fellows from the Institute of Genetics and Development, Chinese Academy of Sciences.
Qingfeng Wu's research group is mainly engaged in neurodevelopment and neuroregulation and metabolism.
Related research has been published in journals such as Cell, Cell Stem Cell, Nat Commun, Cell Reports and PLoS Bio.
The research group is now openly recruiting 1-2 post-doctoral researchers engaged in developmental biology, neurobiology, and bioinformatics.
Salaries and benefits are competitive. Resume delivery (if you are interested, you can send your resume and relevant supporting materials to): https://jinshuju.
net/f/ZqXwZt or scan the QR code to post your resume.
Plate maker: 11 reprint instructions [Non-original article] The copyright of this article belongs to The article is owned by the author, personal forwarding and sharing are welcome, reprinting is prohibited without permission, the author has all legal rights, and offenders must be investigated.
