Abstract

Coordination of the cell cycle with developmental events is crucial for generation of tissues during development and their maintenance in adults. Defects in that coordination can shift the balance of cell fates with devastating clinical effects. Yet our understanding of the molecular mechanisms integrating core cell cycle regulators with developmental regulators remains in its infancy. This work focuses on the interplay between cell cycle and developmental regulators in the Caenorhabditis elegans germline. Key developmental regulators control germline stem cells (GSCs) to self-renew or begin differentiation: FBF RNA–binding proteins promote self-renewal, while GLD RNA regulatory proteins promote meiotic entry. We first discovered that many but not all germ cells switch from the mitotic into the meiotic cell cycle after RNAi depletion of CYE-1 (C. elegans cyclin E) or CDK-2 (C. elegans Cdk2) in wild-type adults. Therefore, CYE-1/CDK-2 influences the mitosis/meiosis balance. We next found that GLD-1 is expressed ectopically in GSCs after CYE-1 or CDK-2 depletion and that GLD-1 removal can rescue cye-1/cdk-2 defects. Therefore, GLD-1 is crucial for the CYE-1/CDK-2 mitosis/meiosis control. Indeed, GLD-1 appears to be a direct substrate of CYE-1/CDK-2: GLD-1 is a phosphoprotein; CYE-1/CDK-2 regulates its phosphorylation in vivo; and human cyclin E/Cdk2 phosphorylates GLD-1 in vitro. Transgenic GLD-1(AAA) harbors alanine substitutions at three consensus CDK phosphorylation sites. GLD-1(AAA) is expressed ectopically in GSCs, and GLD-1(AAA) transgenic germlines have a smaller than normal mitotic zone. Together these findings forge a regulatory link between CYE-1/CDK-2 and GLD-1. Finally, we find that CYE-1/CDK-2 works with FBF-1 to maintain GSCs and prevent their meiotic entry, at least in part, by lowering GLD-1 abundance. Therefore, CYE-1/CDK-2 emerges as a critical regulator of stem cell maintenance. We suggest that cyclin E and Cdk-2 may be used broadly to control developmental regulators.

Highlights

  • Metazoan development coordinates progression through the cell cycle with key developmental events, such as stem cell maintenance, cell fate specification and patterning

  • We find that CYE-1/CDK-2 works with FBF-1 to maintain germline stem cells (GSCs) and prevent their meiotic entry, at least in part, by lowering GLD-1 abundance

  • We find that a posttranscriptional GLD-1 regulator, called FBF-1, works synergistically with cyclin E/Cdk-2 to ensure that GLD-1 is off in germline stem cells

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Summary

Introduction

Metazoan development coordinates progression through the cell cycle with key developmental events, such as stem cell maintenance, cell fate specification and patterning. The C. elegans adult germline provides a superb model to investigate cell cycle controls in a developmental context [8]. Germ cells progress from mitotic divisions at the distal end of the adult gonad through meiotic prophase I in the middle to overt differentiation as sperm or oocyte at the proximal end. The mitotic zone houses a pool of .200 mitotically dividing germ cells, whereas the transition zone contains germ cells that have entered the meiotic cell cycle. As germ cells move proximally through the mitotic zone, most enter meiotic S-phase prior to their entry into the transition zone [10,11,12]. The distal germline presents an orderly maturation from stem cell through transit-amplifying cell to meiotic entry and differentiation

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