Germline Stem Cells and Their Regulation in the Nematode Caenorhabditis elegans

Abstract

C. elegans germline stem cells exist within a stem cell pool that is maintained by a single-celled mesenchymal niche and Notch signaling. Downstream of Notch signaling, a regulatory network governs stem cells and differentiation. Central to that network is the FBF RNA-binding protein, a member of the widely conserved PUF family that functions by either of two broadly conserved mechanisms to repress its target mRNAs. Without FBF, germline stem cells do not proliferate and they do not maintain their naïve, undifferentiated state. Therefore, FBF is a pivotal regulator of germline self-renewal. Validated FBF targets include several key differentiation regulators as well as a major cell cycle regulator. A genomic analysis identifies many other developmental and cell cycle regulators as likely FBF targets and suggests that FBF is a broad-spectrum regulator of the genome with>1,000 targets. A comparison of the FBF target list with similar lists for human PUF proteins, PUM1 and PUM2, reveals ∼200 shared targets. The FBF hub works within a network controlling self-renewal vs. differentiation. This network consists of classical developmental cell fate regulators and classical cell cycle regulators. Recent results have begun to integrate developmental and cell cycle regulation within the network. The molecular dynamics of the network remain a challenge for the future, but models are proposed. We suggest that molecular controls of C. elegans germline stem cells provide an important model for controls of stem cells more broadly.

Proteasome regulation of the chromodomain protein MRG-1 controls the balance between proliferative fate and differentiation in theC. elegansgerm line

“…The balance between the proliferative fate and differentiation in the C. elegans germ line is regulated by a number of factors with activities that are spatially regulated (Hansen and Schedl, 2013;Kershner et al, 2013). GLP-1 signalling activity is presumed to be high in the distal end of the gonad in the PZ, but decreases more proximally as GLD-1 and GLD-2 pathway levels increase, allowing cells to cease proliferation and enter into meiotic prophase (Hansen and Schedl, 2013;Kershner et al, 2013).…”

“…GLP-1 signalling activity is presumed to be high in the distal end of the gonad in the PZ, but decreases more proximally as GLD-1 and GLD-2 pathway levels increase, allowing cells to cease proliferation and enter into meiotic prophase (Hansen and Schedl, 2013;Kershner et al, 2013). This signalling pathway presumably promotes the accumulation and activity of proteins in the distal end of the gonad that are necessary for proliferation and of proteins that are necessary for meiosis more proximally.…”

“…From the very distal end of the gonad to where cells first show signs of entering meiotic prophase is a distance of ∼20 cell diameters (Crittenden et al, 1994;Hansen and Schedl, 2013;Kershner et al, 2013). The primary signal regulating whether a cell adopts a proliferating (mitotic) or differentiating (meiotic) fate is the canonical GLP-1/Notch signalling pathway, with high levels of signalling promoting the proliferative fate and low or absent levels more proximally allowing cells to enter meiotic prophase (Hansen and Schedl, 2013;Kershner et al, 2013) (Fig. 1B,C).…”

Translational activation maintains germline tissue homeostasis during adulthood

“…The Caenorhabditis elegans (C. elegans) germ line is a powerful model system to study the molecular mechanisms underlying this balance of opposing cell fates and tissue maintenance. [1][2][3] In the adult gonad, germ cells form a syncytial tissue and are arranged in a distal-to-proximal organization that reflects subsequent developmental germ cell stages. Most distally and in close proximity to the germline niche (i.e.…”

“…This switch from proliferation-to-differentiation has been termed the mitosis-tomeiosis decision. 2,4 Across species, gene expression regulation in germ cells occurs to a large extent at the post-transcriptional level. Hence, many conserved post-transcriptional RNA regulators have been identified to function in germ cell development.…”