Novel cell survival mechanisms through RNA regulation in the central
nervous system
Ddx20: A novel Olig2 binding protein that is required for proper
development of the central nervous system
Date:
March 14, 2022
Source:
Niigata University
Summary:
This study's findings will help congenital neurological disease
(e.g.
spinal muscular atrophy) specialists better understand the
mechanisms and components involved in CNS development. Notably,
the findings of this work demonstrate unequivocally that Ddx20
is a novel Olig2-interacting factor and a potent suppressor of
the p53 pathway, contributing to the maintenance of neuronal and
oligodendrocyte progenitor cells during CNS development. Therefore,
Ddx20 and Olig2 are promising molecular targets for development
of future therapeutic strategies.
FULL STORY ==========================================================================
This study's findings will help congenital neurological disease
(e.g. spinal muscular atrophy) specialists better understand the
mechanisms and components involved in CNS development. Notably, the
findings of this work demonstrate unequivocally that Ddx20 is a novel Olig2-interacting factor and a potent suppressor of the p53 pathway, contributing to the maintenance of neuronal and oligodendrocyte progenitor cells during CNS development. Therefore, Ddx20 and Olig2 are promising molecular targets for development of future therapeutic strategies.
==========================================================================
The central nervous system, which comprises the brain and spinal cord,
is constructed by the proper proliferation of neural progenitor cells and
their differentiation into neurons and glial cells. The transcription
factor Olig2 is expressed in neural progenitor cells and is essential
for the development of motor neurons and oligodendrocytes, and also
contributes to the proliferation of neural progenitor cells. However,
it has remained unclear how Olig2 regulates these diverse biological
processes. Therefore, this research group searched for a novel Olig2
binding factors and aimed to elucidate the developmental mechanisms
involved in these factors and Olig2.
In a ground-breaking recent study, a team of scientists based at Niigata University, identified a novel Olig2 binding protein called Ddx20
(also known as Gemin3 or DP103) that interacts with Olig2 during neural development. Ddx20 is known as a multifunctional molecule that regulates transcription, RNA splicing, and protein translation. Furthermore,
Ddx20 interacts with SMN, a causative gene of spinal muscular atrophy
(SMA), and is deeply involved in the pathogenesis of SMA. In this study,
the scientists generated Ddx20conditional knockout mice to investigate
the function of Ddx20 during CNS development. They found that apoptosis
occurs rapidly in neural progenitor cells and oligodendrocyte progenitor
cells. The mechanism responsible for the cell death was investigated, and excessive nuclear accumulation of p53, a tumor suppressor gene product,
was found. Interestingly, in Ddx20-deficient mice, the SMN protein was destabilized and the RNA splicing mechanisms were abnormal, leading to
splicing dysregulation of Mdm2, a p53 inhibitor. They proceeded to further understand the mechanism by which Olig2 contributes to neural progenitor
cell proliferation and survival. In these experiments, the authors found
that Ddx20 levels were lower in Olig2 deficient mice than in wild type
mice. Moreover, the SMN protein levels were lower in Olig2-deficient
mice than in wild type mice.
In addition, some spliceosomal RNA and Mdm2 splicing were dysregulated
in Olig2-deficient mice than in wild type mice. Lastly, the p53 was more activated in Olig2-deficient mice than in wild type mice.
In summary, the discovery reported in this study show that Olig2 maintains
the Ddx20-SMN complex involved in the regulation of Mdm2 splicing,
which in turn suppress p53 activation. In an interview with Professor
Hirohide Takebayashi, who led this research at Niigata University, said,
"This study highlights that a transcriptional factor, Olig2, affects not
only transcriptional regulation but also RNA metabolism through Ddx20 stabilization, revealing the diverse functions of Olig2. Importantly,
since Olig2 has been reported to be involved not only in neural
development but also in the progression of glioma and melanoma. On
the other hand, Ddx20 has also been known as an initiator of various
cancers. Therefore, the interaction of these two factors may play a
key role in the development and progression of the cancers. We believe
that further research might provide clues to elucidate the etiology of congenital neurological diseases and cancers, including the development
of therapeutic strategies against them."
========================================================================== Story Source: Materials provided by Niigata_University. Note: Content
may be edited for style and length.
========================================================================== Related Multimedia:
* Schematic_drawing_the_mechanisms_underlying_cell_death ========================================================================== Journal Reference:
1. Norihisa Bizen, Asim K. Bepari, Li Zhou, Manabu Abe, Kenji Sakimura,
Katsuhiko Ono, Hirohide Takebayashi. Ddx20, an Olig2 binding factor,
governs the survival of neural and oligodendrocyte progenitor
cells via proper Mdm2 splicing and p53 suppression. Cell Death &
Differentiation, 2022; DOI: 10.1038/s41418-021-00915-8 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/03/220314095732.htm
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