We study how cells "decide" which direction to take in development by relying on networks of cross-regulatory interactions between RNAs and proteins. To unravel these decisions we monitor the differentiation of pluripotent stem cells, which can turn into any type of cell in the body.

Crossregulation between TDP-43 and NEAT1

Cross-Regulation between TDP-43 and Paraspeckles Promotes Pluripotency Differentiation Transition

Cross-regulation between TDP-43 and NEAT1 enhances the pluripotency-differentiation axis. TDP-43 regulates a switch in the isoforms of the long non-coding RNA NEAT1 during exit from pluripotency. Upon differentiation, the levels of TDP-43 are decreased, which leads to production of the long NEAT1 isoform that condenses many RBPs into a nuclear compartments called 'paraspeckles'. In ESCs, TDP-43 maintains pluripotency by regulating NEAT1 and processing of mRNAs encoding many pluripotency factors. In contrast, the paraspeckle-inducing isoform of NEAT1 promotes differentiation of ESCs and embryos.

We identified a protein (TDP-43) and an RNA (NEAT1) that coordinate the decision of ESCs to exit pluripotency and start differentiating. This work was spearheaded by Miha Modic, who joint our expertise with the lab of Micha Drukker from the Institute of Stem Cell Research (ISF) at the Helmholtz Zentrum München. The work is based on the observation that nuclear compartments named paraspeckles do not occur in pluripotent cells, but are quickly formed during the early differentiation process. He discovered TDP-43 as the key protein in the cell nucleus that orchestrates the appearance of paraspeckles, and demonstrated the roles of both factors in regulating differentiation.

TDP-43 binds to NEAT1 RNA, which exists in two isoforms. TDP-43 promotes the production of short NEAT1 isoform, and in this case, no paraspeckle develop and the cell remains pluripotent. However, opon early differentiation a decrease in TDP-43 enables production of the long isoform of NEAT1 that scaffolds paraspeckles. This crossregulatory networks is essential for stem cells to efficiently coordinate a large number of other genes that enable them to differentiate. We showed that paraspeckles are crucial for efficient differentiation during murine embryonic development.

The discovery of crossregulation between TDP-43 and NEAT1 also provides insights into possible disease mechanisms, particularly the mechanisms of amyotrophic lateral sclerosis (ALS), a progressive neurological disease that affects motor neurons. The role of TDP-43 – as well as the appearance of paraspeckles  – are common features of ALS. In motor neurons, the cells that operate our muscles and are affected by ALS, TDP-43 is often deregulated and forms aggregates; and there is an increased occurrence of the long form of NEAT1, and more paraspeckles can be detected. These mechanisms are regarded as an early sign of ALS – even before patients present with clinically relevant symptoms.


Relevant publications