Abstract
In multicellular organisms, cell type diversity and fate depend on specific sets of transcript isoforms generated by post-transcriptional RNA processing. Here, we used Schmidtea mediterranea, a flatworm with extraordinary regenerative abilities and a large pool of adult stem cells, as an in vivo model to study the role of Uridyl-rich small nuclear RNAs (UsnRNAs), which participate in multiple RNA processing reactions including splicing, in stem cell regulation. We characterized the planarian UsnRNA repertoire, identified stem cell-enriched variants and obtained strong evidence for an increased rate of UsnRNA 3’-processing in stem cells compared to their differentiated counterparts. Consistently, components of the Integrator complex showed stem cell-enriched expression and their depletion by RNAi disrupted UsnRNA processing resulting in global changes of splicing patterns and reduced processing of histone mRNAs. Interestingly, loss of Integrator complex function disrupted both stem cell maintenance and regeneration of tissues. Our data show that the function of the Integrator complex in UsnRNA 3’-processing is conserved in planarians and essential for maintaining their stem cell pool. We propose that cell type-specific modulation of UsnRNA composition and maturation contributes to in vivo cell fate choices, such as stem cell self-renewal in planarians.
Highlights
The cell types composing a multicellular organism differ significantly in morphology and function, despite their identical genetic information
Modifications of messenger RNAs following their transcription play an important role in a stem cell’s decision between self-renewal and differentiation. Since these cells are rare and difficult to access in mammals, the underlying mechanisms have mostly been studied in cultured cells
We employ the planarian flatworm Schmidtea mediterranea that maintains a large pool of highly potent stem cells throughout life as an in vivo model to analyze the function of Uridyl-rich small nuclear RNAs (UsnRNAs), important regulators of multiple messenger RNAs (mRNAs) processing steps, in stem cell regulation
Summary
The cell types composing a multicellular organism differ significantly in morphology and function, despite their identical genetic information These features are determined in a differentiation process starting from a common progenitor, a stem cell, through a number of cell fate decisions. Core components of the spliceosome, including Uridyl-rich small nuclear RNAs (UsnRNAs), were recently implicated in the regulation of pluripotency [10,11]. The studies uncovering these mechanisms employed mammalian embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) in vitro. Comparable cell types are present in vivo only during a short period of development or are exceedingly rare The role of these factors in vivo remains, largely obscure
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