Mo Wei's team at Xiamen University discovered the key role of epigenetics in cerebellar morphogenesis

iNatureBergmann glial cells (BG), Purkinje cells and granular cells (GC) form a close interaction, which is essential for cerebellar morphogenesis and neuronal homeostasis.

However, if there is no complete BG transcriptome map, it is unclear how BG plays a role in this process.

On March 22, 2021, the team of Mo Wei from Xiamen University published a research paper titled "Temporarily Epigenetic Repression in Bergmann Glia Regulates the Migration of Granule Cells" in Advanced Science (IF=16).
The research passed the BG classification of FACS.
High-resolution studies of the transcriptome show that the dynamic expression of genes within a given function and pathway enables BG to assist nerve migration and build a glial network.

The study found that the peak time of GC migration (P7-10) was clearly consistent with the down-regulation of extracellular matrix (ECM) related genes, and that the destruction of Setdb1 at P7-10 of Bdb would cause significant GC migration defects.
The importance of the H3K9me3 repressor complex mediated by Nfix-Setdb1 in the precise regulation of GC migration in vivo.

Therefore, the BG transcriptome map provides insights into the mechanism of BG integration into the cerebellar neural network.

The cerebellum is a well-organized area of ​​the brain that not only controls motor behavior, but also regulates learning, cognitive and emotional processes.

The mature cerebellar cortex is composed of three layers: the inner granular layer (IGL), the Purkinje cell layer (PCL) and the molecular layer (ML); the developing cortex has an additional outer granular layer (EGL).

There are mainly five types of nerve cells in different layers of the cerebellum, including oligodendrocytes (OL), astrocytes, granular cells (GC), Purkinje cells (PC) and Bergmann glial cells (BG) .

The precise location of these cells is essential for the formation of the three-layered structure and the cerebellum, where BG plays a key role in the morphogenesis of the cerebellum.

Cerebellar malformations are related to various neurological diseases, including ataxia, autism spectrum disorder (ASD) and so on.

BG is a type of astrocyte.
It comes from astrocytes and shares some molecular characteristics with astrocytes.

On the other hand, BG becomes a special glia due to its unique position and shape.

The cell body of BG is located at the PCL, and its radial fibers extend through the ML to the pial surface and connect its ends.

BG seems to have maintained this unique form since its early birth.

However, the function of BG will change over time to adapt to the continuous changes of the microenvironment.

BG provides structural support for guiding the migration of newly differentiated GC from EGL to IGL in the first two weeks after birth.

The peak of GC migration is at P7-12, and its damage leads to destructive morphology and paralysis of the cerebellar neural network.

After that, BG is further integrated into neural circuits and plays a key role in information processing, structural integrity maintenance and synaptic connections.

The molecular mechanisms regulating BG function are fragmented.

In BG, neither key transcription factors (TF) nor epigenetic modifications have been fully studied.

Certain signal transduction pathways in BG, such as SHH, Notch and integrin-linked kinase, are assistants of GC migration.

The report also shows the influence of ECM (extracellular matrix) receptor interaction signals on the migration of BG-dependent GCs.

Single-cell sequencing of the developing cerebellum can produce a clear population of BG; however, its characteristics are ambiguous when the depth of the transcriptome is very limited.

BG needs more accurate and in-depth omics analysis.

In this study, two mouse models were identified to label BG and construct the BG transcription landscape from birth to adulthood.

At each stage of development, the function of BG with up-regulated genes is defined through multiple comparisons (UGMC).

The study surprisingly found that developmental progress depends on the dynamic expression of ECM-related genes, and the function of ECM-related genes is related to the development of BG and the migration of GC.

At the peak of cerebellar development (from P7 to P10), GC migration requires genes that are down-regulated in this time window and is completely inhibited by the Nfix-Setdb1 repressor complex.

Setdb1 is one of the main methyltransferases of H3K9me3.

Together, the study has systematically described the molecular characteristics of BG cells at each developmental stage, and further found that the transcriptional inhibition of the Nfix-Setdb1 complex is essential for BG to assist GC migration.

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wiley.
com/doi/10.
1002/advs.
202003164