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Developmental Biology - Cell Differentiation

To Become, Or Just To Be - That is the question

Induced pluripotent stem cells can become any type of cell in the body — or choose to remain in their original form...

In the current edition of Molecular Cell, scientists from the Helmholtz Zentrum München describe how cells choose which path to take. During research, a protein and a ribonucleic acid (RNA) were each identified as significant in that choice. This discovery contributes to a better understanding of amyotrophic lateral sclerosis (ALS), a progressive neurological disease affecting motor neuron control of muscles and glands.
Thanks to their ability to transform into any type of cell in our body, induced pluripotent stem cells (iPSs) also play a role in regenerative medicine.

Induced Pluripotent Stem Cells (iPS) are generated in the laboratory to be reprogrammed into ordinary body cells for research purposes. After reprogramming, iPS stem cells can be turned into any type of body cell through a process known as cellular differentiation.

In order to generate artificial beta cells to treat type 1 diabetes, it is essential to understand all mechanisms underlying cell differentiation. Together with his team, Micha Drukker PhD, Institute of Stem Cell Research, Helmholtz Zentrum München, Neuherberg, Germany, showed how these processes are molecularly controlled.

Two key factors in the cell nucleus

It all begins with a structure in the cell nucleus only visible with the aid of fluorescence microscopy. Paraspeckles are structures that don't always occur. However, when they do appear they consist of special proteins bound to ribonucleic acids (RNAs). Drukker and Miha Modic PhD, hypothesize the appearance of paraspeckles is linked to stem cell differentiation.
"We noticed that nuclear domains, named paraspeckles, do not occur in iPS cells, but are quickly formed during the differentiation process, irrespective of the cell type that we created."

Miha Modic PhD, Institute of Stem Cell Research, Helmholtz Zentrum München; The Francis Crick Institute, London, UK; Department for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK; and member of Drukker's group.

Two key factors in whether cells differentiate or remain pluripotent:

• NEAT1 - a ribonucleic acid (RNA), and
• TDP-43 - a protein that binds to RNA.

NEAT1 also exists in two forms.

• When NEAT1 is a short form, TDP-43 is stabilized: No paraspeckles develop and the cell remains pluripotent without alteration.

• When NEAT1 is a long form, TDP-43 is decreased: Paraspeckles form and iPS cell begins to differentiate.
"This system may control how stem cells make a choice when to differentiate."

Miha Modic PhD, Institute of Stem Cell Research, Helmholtz Zentrum München, Neuherberg, Germany; The Francis Crick Institute, London, UK; Department for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.

Link to Diseases

Drukker believes these findings will do more than just provide a contribution to basic research. "Paraspeckles are linked to many diseases. But, have rarely been examined in the context of developmental and stem cell biology."
In the case of amyotrophic lateral sclerosis (ALS), the role of TDP-43 - as well as the appearance of paraspeckles - is particularly evident. In motor neurons, cells that operate our muscles are affected by ALS. TDP-43 is oddly regulated and forms toxic aggregates; and there is an increased occurrence of the long form of NEAT1, and more paraspeckles can be detected.

These mechanisms are also regarded as an early sign of ALS - even before patients present with clinically relevant symptoms. In the next stage, Drukker and his team hope to examine other cell types for paraspeckles, RNAs and their interactions. By then it will also be apparent whether these newly discovered molecules will be suitable targets for pharmacotherapies.

• TDP-43 maintains pluripotency by regulating expression of pluripotency factors • TDP-43 represses formation of paraspeckles in ESCs by regulating Neat1 • The paraspeckle-inducing isoform of Neat1 promotes • Differentiation of ESCs and embryos • Cross-regulation between TDP-43 and Neat1 enhances pluripotency-differentiation axis.

RNA-binding proteins (RBPs) and long non-coding RNAs (lncRNAs) are key regulators of gene expression, but their joint functions in coordinating cell fate decisions are poorly understood. Here we show that the expression and activity of the RBP TDP-43 and the long isoform of the lncRNA Neat, the scaffold of the nuclear compartment ‘‘paraspeckles,’’ are reciprocal in pluripotent and differentiated cells because of their cross-regulation. In pluripotent cells, TDP-43 represses the formation of paraspeckles by enhancing the polyadenylated short isoform of Neat1. TDP-43 also promotes pluripotency by regulating alternative polyadenylation of transcripts encoding pluripotency factors, including Sox2, which partially protects its 30 UTR from miR-21-mediated degradation. Conversely, paraspeckles sequester TDP-43 and other RBPs from mRNAs and promote exit from pluripotency and embryonic patterning in the mouse. We demonstrate that cross-regulation between TDP-43 and Neat1 is essential for their efficient regulation of a broad network of genes and, therefore, of pluripotency and differentiation.

Miha Modic, Markus Grosch, Gregor Rot, Silvia Schirge, Tjasa Lepko, Tomohiro Yamazaki, Flora C.Y. Lee, Ejona Rusha,1 Dmitry Shaposhnikov,1 Michael Palo,3,4 Juliane Merl-Pham,8 Davide Cacchiarelli, Boris Rogelj, Stefanie M. Hauck, Christian von Mering, Alexander Meissner, Heiko Lickert, Tetsuro Hirose, Jernej Ule and Micha Drukker.

The authors would like to thank Alfredo Castello and Rickie Patani for critical reading of the manuscript. For generous reagent gifts, we are grateful to Derk ten Berge, Philip C. Wong, Shinichi Nakagawa, Michael Kyba, Dieter Edbauer and Bettina Schmidt. We would like to thank to Anna Pertek and Tajda Klobucar for technical assistance. We are grateful to Nejc Haberman for sequence motif identification, Igor Ruiz de los Mozos for iCount analysis, and Michael Ziller and Joel Ryan for methodological advice. This work was supported by the European Research Council (206726-CLIP and 617837 - Translate to J.U.), Slovenian Research Agency (P4-0127, JS-6789, J3-8201 and J3-9263 to B.R.), an IMPRS Max Planck Society fellowship (to M.M.), the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001002), the UK Medical Research Council (FC001002), and the Wellcome Trust (FC001002), and Seed Funding Award by the UHU Network (UWA, Helmholtz, UCL, to MD).

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May 8 2019   Fetal Timeline   Maternal Timeline   News  

Paraspeckles (RED) appear just before and after cell differentiation.
CREDIT Helmholtz Zentrum München

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