Abstract
Central questions in regenerative biology include how stem cells are maintained and how they transition from self-renewal to differentiation. Germline stem cells (GSCs) in Caeno-rhabditis elegans provide a tractable in vivo model to address these questions. In this system, Notch signaling and PUF RNA binding proteins, FBF-1 and FBF-2 (collectively FBF), maintain a pool of GSCs in a naïve state. An open question has been how Notch signaling modulates FBF activity to promote stem cell self-renewal. Here we report that two Notch targets, SYGL-1 and LST-1, link niche signaling to FBF. We find that SYGL-1 and LST-1 proteins are cytoplasmic and normally restricted to the GSC pool region. Increasing the distribution of SYGL-1 expands the pool correspondingly, and vast overexpression of either SYGL-1 or LST-1 generates a germline tumor. Thus, SYGL-1 and LST-1 are each sufficient to drive “stemness” and their spatial restriction prevents tumor formation. Importantly, SYGL-1 and LST-1 can only drive tumor formation when FBF is present. Moreover, both proteins interact physically with FBF, and both are required to repress a signature FBF mRNA target. Together, our results support a model in which SYGL-1 and LST-1 form a repressive complex with FBF that is crucial for stem cell maintenance. We further propose that progression from a naïve stem cell state to a state primed for differentiation relies on loss of SYGL-1 and LST-1, which in turn relieves FBF target RNAs from repression. Broadly, our results provide new insights into the link between niche signaling and a downstream RNA regulatory network and how this circuitry governs the balance between self-renewal and differentiation.
Highlights
The balance between stem cell self-renewal and differentiation is pivotal for normal development, adult homeostasis, and regeneration
Stem cells lie at the heart of metazoan development, regeneration, and tissue homeostasis, but the molecular basis of their regulation is poorly understood in their natural context
To visualize SYGL-1 and LST-1 proteins, we generated epitope-tagged versions of sygl-1 and lst-1, including single-copy transgenes using MosSCI [20,21,22] and endogenous alleles using CRISPR-Cas9 [23, 24] (Fig 1C and 1D). These epitope-tagged SYGL-1 and LST-1 proteins were functional: they maintain Germline stem cells (GSCs) when tested in appropriate mutant backgrounds (S1D and S1E Fig)
Summary
The balance between stem cell self-renewal and differentiation is pivotal for normal development, adult homeostasis, and regeneration. Aberrant stem cell regulation can cause disease, including human degenerative disorders and cancers [1]. Stem cell daughters can exist in a “naïve” multipotent state or a “primed” state that has been triggered to differentiate, typically via transit-amplification [2,3,4]. Challenges have included the complexity of their niches [8] and diversity of stem cell states (e.g. quiescent vs proliferative) [9]. Understanding how stem cell daughters are regulated to remain naïve or transition to a primed state can greatly benefit from a tractable model with well-defined niche and stem cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
