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Drosha and its RNA binding partners in neurogenesis
Third-party funded project
Project title Drosha and its RNA binding partners in neurogenesis
Principal Investigator(s) Taylor, Verdon
Project Members Lampada, Aikaterini
Iffländer, Niklas
Organisation / Research unit Departement Biomedizin / Embryology and Stem Cell Biology (Taylor)
Project start 01.01.2019
Probable end 31.12.2022
Status Completed
Abstract

Neural stem cells (NSCs) generate the central nervous system (CNS) and new neurons and glia in distinct brain regions of adult mammals. Regulation of NSC maintenance and differentiation is crucial but how they are controlled remain unclear. NSCs self-renew to maintain the progenitor pool, but also generate committed offspring in a regulated fashion. The balance between proliferation and differentiation guarantees brain formation, life-long neurogenesis, and prevents tumor formation. A detailed understanding of NSC biology has important implications for comprehending brain malformations, age-related disorders, and neurological diseases. The potential of NSCs for regeneration and rejuvenation of the brain emphasize the need to expand our basic knowledge of their biology. Over the last three decades, we have learnt a lot about the signaling pathways that can regulate NSC activity. Some of the signaling pathways and transcriptional networks controlling NSC fate are intimately linked, for example the Notch pathway and proneural transcription factors. However, it is becoming clear that post-transcriptional regulation of protein expression regulates NSC fate. My lab has focused on the role of signaling in NSC maintenance. By combining transgenic mice with analysis of NSC behavior during homeostasis, physical activity, degeneration, regeneration and aging in vivo and in vitro, we determined that NSCs are heterogeneous even within the same niche. Recently, we found that the adult ventricular-subventricular zone (V-SVZ) and subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) contain quiescent, active and dormant NSCs and loss of active NSCs is a primary cause for age-related reductions in neurogenesis. We found that the RNAseIII Drosha, a component of the microRNA (miRNA) microprocessor (MP), synergizes with Notch and plays fundamental roles in NSC maintenance and differentiation through a novel miRNA-independent mechanism. Drosha directly targets stem-loop hairpin structures in the mRNA of the proneural transcription factor Neurog2 during embryonic development and NFIB in adult NSCs and regulates fate and differentiation. Thus, post-transcriptional regulation is a novel and critical process in NSC differentiation. As all cells ubiquitously express Drosha, we questioned how Drosha activity is controlled in order that its mRNA targets can evade processing once the protein is required. By cross-linked RNA immunoprecipitation (CLIP) of endogenous Drosha, we have identified additional mRNA targets in NSCs. Using RNA pull-down assays and double mass-spectroscopy (MS/MS), we identified the proteins associated with Drosha-targeted mRNAs in NSCs. We hypothesize that these proteins, together with Drosha, regulate RNA stability and translation, and are crucial for brain development and homeostatic neurogenesis. We have developed screening systems to quantify Drosha processing of target mRNAs and to assess the functions of the RNA binding proteins (RBPs) and Drosha partners in NSCs. RBPs are a major family in of proteins and are encode by at least 7.5% of the genes in the genome. Many have links to human neurological disease, including some that bind Drosha and its targets. However, the functions of many of these RBPs in controlling brain development and neurogenesis are not known. RNA-Seq analysis revealed differential expression of many RBPs during development and adult neurogenesis. Here we will address the functions of Drosha associated proteins and RBPs that interact with its target mRNAs in NSCs of the embryonic and adult CNS. The aim of this project is to address potential novel mechanisms and actors in post-transcriptional regulation of stem cell maintenance, differentiation and fate commitment using NSCs and neurogenesis as model systems.

Financed by Swiss National Science Foundation (SNSF)
   

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29/03/2024