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Review
. 2016 Feb;49(2):93-8.
doi: 10.5483/bmbrep.2016.49.2.135.

A systematic mRNA control mechanism for germline stem cell homeostasis and cell fate specification

Myon-Hee Lee  1 , Srivalli Swathi Mamillapalli  2 , Brett D Keiper  3 , Dong Seok Cha  4
Affiliations
Review

A systematic mRNA control mechanism for germline stem cell homeostasis and cell fate specification

Myon-Hee Lee et al. BMB Rep. 2016 Feb.

Abstract

Germline stem cells (GSCs) are the best understood adult stem cell types in the nematode Caenorhabditis elegans, and have provided an important model system for studying stem cells and their cell fate in vivo, in mammals. In this review, we propose a mechanism that controls GSCs and their cell fate through selective activation, repression and mobilization of the specific mRNAs. This mechanism is acutely controlled by known signal transduction pathways (e.g., Notch signaling and Ras-ERK MAPK signaling pathways) and P granule (analogous to mammalian germ granule)-associated mRNA regulators (FBF-1, FBF-2, GLD-1, GLD-2, GLD-3, RNP-8 and IFE-1). Importantly, all regulators are highly conserved in many multi-cellular animals. Therefore, GSCs from a simple animal may provide broad insight into vertebrate stem cells (e.g., hematopoietic stem cells) and their cell fate specification. [BMB Reports 2016; 49(2): 93-98].

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Figures

Fig. 1.
Fig. 1.. C. elegans germline and GSC regulation. (A) Schematic of an adult C. elegans hermaphrodite gonad. Somatic DTC is located at the distal end. Cells at the distal end of the germline, including GSCs, divide mitotically (yellow). As cells move proximally, they enter meiosis (green) and differentiate into either sperm (blue) or oocytes (pink). (B) Schematic of an adult C. elegans male gonad. Two somatic DTCs reside at the distal ends of the adult male gonad. In the male germline, all GSCs differentiate into sperm (blue). (C) A simplified model for GSCs and their differentiation. GSC self-renew and differentiate into either sperm or egg. GLP-1/Notch signaling promotes GSC self-renewal and proliferation by inhibiting differentiation. *, inferred actual GSCs.
Fig. 2.
Fig. 2.. A systematic RNA selection mechanism. (A) Transcriptional activation by GLP-1/Notch signaling. DTCs function a GSC niche. LAG-2, a Notch ligand, is expressed on the DTC membrane. Notch receptor, GLP-1, is expressed on the membrane of GSC and mitotically dividing germ cells. Upon Notch activation, the GLP-1 intracellular domain (ICD) is trans-located from membrane to nucleus and forms a ternary complex with transcription activators, “LAG-1 and LAG-3” to activate the expression of target genes. Once GSCs move away from a DTC, LAG-1 interacts with transcription corepressors (CoRs) to repress the expression of target genes. (B) GSC homeostasis. GLP-1/Notch signaling activates the expression of target genes, including FBF-2. FBF-2 acts as a regulatory hub for the proliferation and differentiation of GSCs. (C) Germ cell fate specification. FBF proteins inhibit the translation of the selected target mRNAs and translational activators (e.g., GLD-2, GLD-3, RNP-8, and IFE-1) promote the translation of the selected target mRNAs. (D) FBF proteins mediate mRNA repression. FBF proteins bind to the FBE(s) in target mRNAs and associate with CCF-1 or/and Ago to repress the stability or/and translation of target mRNAs. (E) GLD-2 and IFE-1-mediated mRNA activation. GLD-2 and its partners (GLD-3 or RNP-8) promote the stability of target mRNAs, as well as, IFE-1 and the translation initiation complex promote the translation of target mRNAs. Italic letters indicate mRNAs and capital letters indicate proteins.
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