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Written by Yugeng
EditorWang Duoyu
TypesettingWater into text
As we all know, every animal has its own brain, but the human brain is unique, endowing humans with thinking, speaking, perceiving, and a range of behaviors that control everything
an individual thinks and does throughout his life.
The human brain is considered the most complex organ
in the life sciences.
So far, there are still too many long-unsolved mysteries
.
In past studies, scientists have made some progress by studying animal brains; Unfortunately, these findings don't translate directly to humans
.
Because the human brain has unique characteristics
that distinguish it from other species.
In addition, recent cell atlases have provided high-resolution descriptions of brain cell composition in mouse and human development, but due to the difficulty of obtaining brain tissue in the earliest stages of life and the lack of methods to systematically manipulate gene function, studying the mechanisms that control human brain development has always been a major challenge
.
October 5, 2022, Dr.
Barbara Treutlein, Dr.
Zhisong Ho and J.
Gray Camp of Roche Pharmaceuticals at ETH Zurich, Switzerland The research team led by the Ph.
D.
published a research paper in Nature titled: Inferring and perturbing cell fate regulomes in human brain organoids.
The study established a multi-omics map of human brain organoid development, demonstrating for the first time that the transcription factor GLI3 is involved in the formation
of human forebrain patterns.
The study provides a framework
for how to reconstruct human developmental biology using mannequin systems and single-cell techniques.
In recent years, human stem cells have been used to generate complex brain organoids in a controlled culture environment It opens up new avenues
for understanding the mechanisms of human brain development.
The brain or non-directed neural organoids can develop from embryonic stem cells or induced pluripotent stem cells into three-dimensional neural epithelial cells that can self-pattern, regionalize, and eventually form neurons
in different brain regions.
At present, brain organoids have been successfully used to simulate other neurodevelopmental disorders
such as microcephaly and autism.
However, the gene regulatory network that coordinates the early development of the human brain under normal and disturbing conditions remains unknown
.
In the new study, the team generated single-cell transcriptome and single-cell-available chromatin analysis data
during the development of human brain organoids.
This dataset is derived from 11 time points of 3 human iPS cell lines and 1 embryonic stem cell line, covering the 2-month developmental process, including embryoid body formation, neuroectoderm induction, neuroepithelialization, neural progenitor cell patterns, and neurogenesis
.
The researchers used the data to build a multi-omic map of brain organoid development, revealing key stages of developmental hierarchy and fate determination, as well as a molecular fingerprint
of each cell within the organoid.
However, each cell in an organoid has more than 20,000 genes, and each organoid is made up of
thousands of cells.
Thus, a huge matrix
is produced.
To analyze all this massive multidimensional data and predict gene regulatory mechanisms, the researchers developed a framework program, Pando, that combines multiomics data and prediction of transcription factor binding sites to extrapolate the entire gene regulatory network
that describes organoid development.
Using CRISPR-Cas9 gene-editing technology, the researchers selectively switched off a gene in each cell, with a total of 24 genes being switched off
simultaneously throughout the organoid.
This allowed them to observe the role
that specific genes play in brain development.
The researchers say the method could be used to screen genes associated with disease and to see how the gene affects
the development of different cells within organs.
To test their theory, the researchers focused on the transcription factor GLI3
.
GLI3 is a regulatory factor of mouse cortical development, and mutations in this gene can cause malformations
in the central nervous system of mice.
In the past, the role of GLI3 in human neurodevelopment was unexplored, but mutations in this gene have been known to cause diseases
such as Greig polydactyly syndrome and Pallister Hall syndrome.
To confirm GLI3's involvement in the establishment of cell fate in the human environment, as well as to examine the underlying developmental mechanisms, the researchers validated GLI3 by establishing a GLI3 knockout iPS cell line and a control wild-type cell line through CRISPR-Cas9 gene editing, and generating two independent brain organoids A key role in the fate of human dorsal terminal brain cells, and further identified the contribution of
GLI3 in medial ganglion bulge (MGE) and lateral/caudal ganglion (LGE/CGE) neurons.
The loss of GLI3 can affect the further development
of organoids.
Barbara Treutlein, corresponding author of the paper, said the study is the first to demonstrate that the GLI3 gene is involved in the formation of human forebrain patterns, which have only been found in mice before
.
This research allows you to use genome-wide data from multiple single cells to infer the role played by a single gene; Moreover, these model systems in Petri dishes do reflect the role
of GLI3 in mouse developmental biology.
Brain organoids from human stem cells under fluorescence microscopy: GLI3 (purple) labeled neuronal (green) precursor cells
in the forebrain region The team also discovered how the medium forms tissues in a self-organizing manner, Its structure is comparable
to that of the human brain in terms of morphology as well as gene regulation and pattern formation.
Barbara Treutlein says organoids like this are indeed an excellent way to
study the biology of human development.
Another advantage of these organoid studies, which are composed of human cellular material, is that they can be transferred to humans, not only for basic developmental biology, but also for studying the role
of genes in diseases or developmental brain diseases.
For example, the team is using this organoid to study the genetic causes
of autism and periventricular ectopia.
In addition, organoids can also be used for drug testing and culturing components of
transplantable organs.
Together, these data reveal the extraordinary potential
of multimodal single-cell genomics and organoid technologies in understanding the gene regulatory programs of human brain development.
The study provides a framework
for how to reconstruct human developmental biology using mannequin systems and single-cell techniques.
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