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Responsible editor | The neuron is the basic functional unit that constitutes the structure of the nervous system.
Neurons in the central nervous system have two typical organizational structures, one is a laminar structure, such as the cerebral cortex (cortex); the other is a nuclear structure, such as the hypothalamus (hypothalamus) ).
The molecular and cellular mechanisms of the development and formation of layered structures have been studied extensively and in-depth, while our research on the development and formation mechanisms of nucleus structures is relatively rare.
The hypothalamus is a relatively conserved brain area in the evolution of animal brains.
It has a large number of nucleus and numerous neuronal subtypes [1].
The hypothalamus is also an indispensable brain area for the brain to regulate animal homeostatic state and primitive behavior.
It has a key regulatory role in endocrine, sleep and circadian rhythm, reproduction and sexual behavior, and diet and energy balance.
【2】.
These complex and delicate regulatory functions of the hypothalamus depend on its large number of nuclei and many types of neurons.
However, we don't know much about the mechanism of hypothalamic neuron generation and organization, and the developmental establishment of hypothalamic nuclei.
On February 17, 2021, the team of Professor Hongjun Song from the University of Pennsylvania published online research work entitled "Decoding neuronal composition and ontogeny of individual hypothalamic nuclei" in Neuron.
The study revealed the neuron type composition of several mouse hypothalamic nuclei, and discovered the mechanism of generation of the diversity of hypothalamic neuron types and the basic laws of the development and formation of hypothalamic nuclei.
This study first used transcription factors to label neurons in the arcuate nucleus (Arc), ventromedial hypothalamus (VMH), and tuberal nucleus (TuN) of the postnatal (postnatal) hypothalamus.
And classification.
The authors found that the combination of three sets of transcription factors, TBX3/OTP/DLX, NKX2.
1/SF1 and OTP/DLX, can label almost all neurons in the arcuate nucleus, ventromedial nucleus and tubercle nucleus, respectively.
The combination of TBX3/OTP/DLX can distinguish four types of arcuate nucleus neurons, which are named Arc1-4 (see Figure 1).
Further studies have shown that Arc1, Arc2 and Arc4 neurons have a one-to-one correspondence with POMC neurons, NPY/AgRP neurons and TH neurons that have important regulatory effects on dietary behavior or hormone secretion, respectively.
Figure 1.
The types and distribution of hypothalamic arcuate nucleus (Arc) neurons.
The author also found that the combination of NKX2.
1/SF1 can distinguish the ventromedial nucleus into the inner VMHdm/c area and the outer VMHvl area.
The OTP/DLX combination can distinguish three types of nodular nucleus neurons, which are named TuN1-3 (see Figure 2).
Further research confirmed that all ventromedial nucleus neurons are glutamatergic neurons, and all nodular nucleus neurons are γ-aminobutyric acid (GABAergic) neurons.
Figure 2.
The types and distribution of neurons in the ventromedial hypothalamic nucleus (VMH) and tubercle nucleus (TuN).
Next, the author studied the development of the hypothalamic nucleus.
Compared with neuropeptides and other markers, transcription factors are expressed earlier in the process of neuron generation and differentiation.
Therefore, the use of transcription factors can track the origin and migration of neurons during embryonic development.
The author found that the four types of arcuate nucleus neurons all originated in a common area in the embryonic stage, and named it pArc (progenitor domain of arcuate nucleus).
What’s more interesting is that the four arcuate nucleus neurons are produced in a mosaic pattern, that is, the four arcuate nucleus neurons are interlaced with each other, and there is no specific pArc subregion to produce different neurons.
Types of.
Using the nucleoside analogue BrdU to track the birth date (birth-dating) found that four arcuate nucleus neurons are produced simultaneously (simultaneous).
In order to further understand the cellular mechanism of this mosaic pattern, the author conducted a single-cell clonal lineage-tracing analysis experiment.
This experiment can label individual hypothalamic embryonic neural stem cells (radial glia progenitor, RGP) at the early stage of the mouse embryo, and then analyze the neuron types produced by the labeled radial glia cells after birth .
The authors found that a single radial glial cell in the pArc region is a multipotent neural stem cell, which can produce at least two arcuate nucleus neuron types, and very rarely a single arcuate nucleus neuron type (see Figure 3).
Further analysis found that a single radial glial cell in the pArc region can produce a combination of multiple neuron types among the four arcuate nucleus neuron types.
Figure 3.
The generation of hypothalamic arcuate nucleus (Arc) neurons and the development of arcuate nucleus.
Then, the author also studied the development and formation of hypothalamic ventromedial nucleus and tubercle nucleus.
In the central nervous system, the two main neuronal types glutamatergic neurons and gamma-aminobutyric neurons usually originate from different progenitor domains in the embryonic stage [3-5].
The author was surprised to find that the glutamatergic ventromedial nucleus neurons and the gamma-aminobutyric acid nodular nucleus neurons originated from the same precursor cell area in the embryonic stage, and named them pVMH (progenitor domain of ventromedial hypothalamus).
Further research found that ventromedial nucleus neurons and nodular nucleus neurons are also generated in a mosaic pattern.
BrdU tracking experiments show that the neurons in the ventromedial nucleus and the tubercle nucleus are organized in an outside-in pattern, that is, the early neurons are mainly distributed on the outside of the ventromedial nucleus (VMHvl) and the tubercle nucleus , And late-generation neurons are mainly distributed on the inner side of the ventromedial nucleus (VMHdm/c).
Subsequently, the authors performed a single-cell clonal lineage analysis on the pVMH region.
This study showed that a single radial glial cell in the pVMH region can simultaneously produce glutamatergic ventromedial nucleus neurons and gamma-aminobutyric acid nodular nucleus neurons.
Further analysis revealed that a single radial glial cell in the pVMH region is a pluripotent neural stem cell, which can produce at least two of the three types of neurons: lateral ventromedial nucleus neurons, medial ventromedial nucleus neurons and tubercle nucleus neurons.
Types, and can generate a combination of various neuron types in the three neuron types (see Figure 4).
Figure 4.
The generation of hypothalamic ventromedial nucleus (VMH) and tubercle nucleus (TuN) neurons and the development of the ventromedial nucleus and tubercle nucleus.
In summary, first of all, this study used a combination of different transcription factors to identify Neurons in the arcuate nucleus of the hypothalamus, ventromedial nucleus and tubercle nucleus and their neuron types; secondly, the phenomenon that the pArc region and the pVMH region generate multiple neuron types in a mosaic pattern is explained, and the contribution of the pArc region is found Arcuate nucleus neurons, and the pVMH region contributes to both glutamatergic ventromedial nucleus neurons and gamma-aminobutyric acid nodular nucleus neurons, thus also solving the embryonic origin of nodular nucleus neurons; Finally, the pluripotency of single radial glial cells in the pArc region and pVMH region and the diversity of these radial glial cell lineages are revealed. Given that the central nervous system has a large number of nucleus structure brain regions, and we do not know much about the development and formation of these nuclei, the phenomena and basic laws discovered in this study are useful for studying the neuronal diversity of other nuclei.
The production mechanism and developmental formation mechanism have important reference significance.
The first author of the paper is Dr.
Ma Tong, and the corresponding author is Professor Song Hongjun.
Professor Z.
Josh Huang from Duke University, Professor Yang Zhengang from the Institute of Brain Science at Fudan University, and Professor Jae W.
Lee from the University of Buffalo contributed to this research. Original link https://doi.
org/10.
1016/j.
neuron.
2021.
01.
026 Platemaker: Qijiang References 1.
Romanov, RA, Alpár, A.
, Hökfelt, T.
, and Harkany, T.
(2019) .
Unified Classification of Molecular, Network, and Endocrine Features of Hypothalamic Neurons.
Annu Rev Neurosci 42, 1-26.
2.
Saper, CB, and Lowell, BB (2014).
The hypothalamus.
Curr Biol 24, R1111-1116.
3.
Alaynick, WA , Jessell, TM, and Pfaff, SL (2011).
SnapShot: spinal cord development.
Cell 146, 178-178.
e171.
4.
Gray, PA (2008).
Transcription factors and the genetic organization of brain stem respiratory neurons.
J Appl Physiol (1985) 104, 1513-1521.
5.
Marin, O.
, and Muller, U.
(2014).
Lineage origins of GABAergic versus glutamatergic neurons in the neocortex.
Curr Opin Neurobiol 26, 132-141.
Neurons in the central nervous system have two typical organizational structures, one is a laminar structure, such as the cerebral cortex (cortex); the other is a nuclear structure, such as the hypothalamus (hypothalamus) ).
The molecular and cellular mechanisms of the development and formation of layered structures have been studied extensively and in-depth, while our research on the development and formation mechanisms of nucleus structures is relatively rare.
The hypothalamus is a relatively conserved brain area in the evolution of animal brains.
It has a large number of nucleus and numerous neuronal subtypes [1].
The hypothalamus is also an indispensable brain area for the brain to regulate animal homeostatic state and primitive behavior.
It has a key regulatory role in endocrine, sleep and circadian rhythm, reproduction and sexual behavior, and diet and energy balance.
【2】.
These complex and delicate regulatory functions of the hypothalamus depend on its large number of nuclei and many types of neurons.
However, we don't know much about the mechanism of hypothalamic neuron generation and organization, and the developmental establishment of hypothalamic nuclei.
On February 17, 2021, the team of Professor Hongjun Song from the University of Pennsylvania published online research work entitled "Decoding neuronal composition and ontogeny of individual hypothalamic nuclei" in Neuron.
The study revealed the neuron type composition of several mouse hypothalamic nuclei, and discovered the mechanism of generation of the diversity of hypothalamic neuron types and the basic laws of the development and formation of hypothalamic nuclei.
This study first used transcription factors to label neurons in the arcuate nucleus (Arc), ventromedial hypothalamus (VMH), and tuberal nucleus (TuN) of the postnatal (postnatal) hypothalamus.
And classification.
The authors found that the combination of three sets of transcription factors, TBX3/OTP/DLX, NKX2.
1/SF1 and OTP/DLX, can label almost all neurons in the arcuate nucleus, ventromedial nucleus and tubercle nucleus, respectively.
The combination of TBX3/OTP/DLX can distinguish four types of arcuate nucleus neurons, which are named Arc1-4 (see Figure 1).
Further studies have shown that Arc1, Arc2 and Arc4 neurons have a one-to-one correspondence with POMC neurons, NPY/AgRP neurons and TH neurons that have important regulatory effects on dietary behavior or hormone secretion, respectively.
Figure 1.
The types and distribution of hypothalamic arcuate nucleus (Arc) neurons.
The author also found that the combination of NKX2.
1/SF1 can distinguish the ventromedial nucleus into the inner VMHdm/c area and the outer VMHvl area.
The OTP/DLX combination can distinguish three types of nodular nucleus neurons, which are named TuN1-3 (see Figure 2).
Further research confirmed that all ventromedial nucleus neurons are glutamatergic neurons, and all nodular nucleus neurons are γ-aminobutyric acid (GABAergic) neurons.
Figure 2.
The types and distribution of neurons in the ventromedial hypothalamic nucleus (VMH) and tubercle nucleus (TuN).
Next, the author studied the development of the hypothalamic nucleus.
Compared with neuropeptides and other markers, transcription factors are expressed earlier in the process of neuron generation and differentiation.
Therefore, the use of transcription factors can track the origin and migration of neurons during embryonic development.
The author found that the four types of arcuate nucleus neurons all originated in a common area in the embryonic stage, and named it pArc (progenitor domain of arcuate nucleus).
What’s more interesting is that the four arcuate nucleus neurons are produced in a mosaic pattern, that is, the four arcuate nucleus neurons are interlaced with each other, and there is no specific pArc subregion to produce different neurons.
Types of.
Using the nucleoside analogue BrdU to track the birth date (birth-dating) found that four arcuate nucleus neurons are produced simultaneously (simultaneous).
In order to further understand the cellular mechanism of this mosaic pattern, the author conducted a single-cell clonal lineage-tracing analysis experiment.
This experiment can label individual hypothalamic embryonic neural stem cells (radial glia progenitor, RGP) at the early stage of the mouse embryo, and then analyze the neuron types produced by the labeled radial glia cells after birth .
The authors found that a single radial glial cell in the pArc region is a multipotent neural stem cell, which can produce at least two arcuate nucleus neuron types, and very rarely a single arcuate nucleus neuron type (see Figure 3).
Further analysis found that a single radial glial cell in the pArc region can produce a combination of multiple neuron types among the four arcuate nucleus neuron types.
Figure 3.
The generation of hypothalamic arcuate nucleus (Arc) neurons and the development of arcuate nucleus.
Then, the author also studied the development and formation of hypothalamic ventromedial nucleus and tubercle nucleus.
In the central nervous system, the two main neuronal types glutamatergic neurons and gamma-aminobutyric neurons usually originate from different progenitor domains in the embryonic stage [3-5].
The author was surprised to find that the glutamatergic ventromedial nucleus neurons and the gamma-aminobutyric acid nodular nucleus neurons originated from the same precursor cell area in the embryonic stage, and named them pVMH (progenitor domain of ventromedial hypothalamus).
Further research found that ventromedial nucleus neurons and nodular nucleus neurons are also generated in a mosaic pattern.
BrdU tracking experiments show that the neurons in the ventromedial nucleus and the tubercle nucleus are organized in an outside-in pattern, that is, the early neurons are mainly distributed on the outside of the ventromedial nucleus (VMHvl) and the tubercle nucleus , And late-generation neurons are mainly distributed on the inner side of the ventromedial nucleus (VMHdm/c).
Subsequently, the authors performed a single-cell clonal lineage analysis on the pVMH region.
This study showed that a single radial glial cell in the pVMH region can simultaneously produce glutamatergic ventromedial nucleus neurons and gamma-aminobutyric acid nodular nucleus neurons.
Further analysis revealed that a single radial glial cell in the pVMH region is a pluripotent neural stem cell, which can produce at least two of the three types of neurons: lateral ventromedial nucleus neurons, medial ventromedial nucleus neurons and tubercle nucleus neurons.
Types, and can generate a combination of various neuron types in the three neuron types (see Figure 4).
Figure 4.
The generation of hypothalamic ventromedial nucleus (VMH) and tubercle nucleus (TuN) neurons and the development of the ventromedial nucleus and tubercle nucleus.
In summary, first of all, this study used a combination of different transcription factors to identify Neurons in the arcuate nucleus of the hypothalamus, ventromedial nucleus and tubercle nucleus and their neuron types; secondly, the phenomenon that the pArc region and the pVMH region generate multiple neuron types in a mosaic pattern is explained, and the contribution of the pArc region is found Arcuate nucleus neurons, and the pVMH region contributes to both glutamatergic ventromedial nucleus neurons and gamma-aminobutyric acid nodular nucleus neurons, thus also solving the embryonic origin of nodular nucleus neurons; Finally, the pluripotency of single radial glial cells in the pArc region and pVMH region and the diversity of these radial glial cell lineages are revealed. Given that the central nervous system has a large number of nucleus structure brain regions, and we do not know much about the development and formation of these nuclei, the phenomena and basic laws discovered in this study are useful for studying the neuronal diversity of other nuclei.
The production mechanism and developmental formation mechanism have important reference significance.
The first author of the paper is Dr.
Ma Tong, and the corresponding author is Professor Song Hongjun.
Professor Z.
Josh Huang from Duke University, Professor Yang Zhengang from the Institute of Brain Science at Fudan University, and Professor Jae W.
Lee from the University of Buffalo contributed to this research. Original link https://doi.
org/10.
1016/j.
neuron.
2021.
01.
026 Platemaker: Qijiang References 1.
Romanov, RA, Alpár, A.
, Hökfelt, T.
, and Harkany, T.
(2019) .
Unified Classification of Molecular, Network, and Endocrine Features of Hypothalamic Neurons.
Annu Rev Neurosci 42, 1-26.
2.
Saper, CB, and Lowell, BB (2014).
The hypothalamus.
Curr Biol 24, R1111-1116.
3.
Alaynick, WA , Jessell, TM, and Pfaff, SL (2011).
SnapShot: spinal cord development.
Cell 146, 178-178.
e171.
4.
Gray, PA (2008).
Transcription factors and the genetic organization of brain stem respiratory neurons.
J Appl Physiol (1985) 104, 1513-1521.
5.
Marin, O.
, and Muller, U.
(2014).
Lineage origins of GABAergic versus glutamatergic neurons in the neocortex.
Curr Opin Neurobiol 26, 132-141.
