DAZL Limits Pluripotency, Differentiation, and Apoptosis in Developing Primordial Germ Cells

• Published in: Stem cell reports Vol. 3; no. 5; pp. 892 - 904
• Main Authors: Chen, Hsu-Hsin, Welling, Maaike, Bloch, Donald B., Muñoz, Javier, Mientjes, Edwin, Chen, Xinjie, Tramp, Cody, Wu, Jie, Yabuuchi, Akiko, Chou, Yu-Fen, Buecker, Christa, Krainer, Adrian, Willemsen, Rob, Heck, Albert J., Geijsen, Niels
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.11.2014; Elsevier
• Subjects: Animals; Animals, Genetically Modified; Apoptosis - genetics; Cell Differentiation - genetics; Cells, Cultured; Embryo, Mammalian - cytology; Embryo, Mammalian - embryology; Embryo, Mammalian - metabolism; Embryonic Stem Cells - metabolism; Gene Expression Profiling; Gene Expression Regulation, Developmental; Gene Regulatory Networks; Germ Cells - metabolism; Immunoblotting; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Mice; Microscopy, Confocal; Oligonucleotide Array Sequence Analysis; Pluripotent Stem Cells - metabolism; Resource; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2014.09.003

The scarcity of primordial germ cells (PGCs) in the developing mammalian embryo hampers robust biochemical analysis of the processes that underlie early germ cell formation. Here, we demonstrate that DAZL, a germ cell-specific RNA binding protein, is a robust PGC marker during in vitro germ cell development. Using Dazl-GFP reporter ESCs, we demonstrate that DAZL plays a central role in a large mRNA/protein interactive network that blocks the translation of core pluripotency factors, including Sox2 and Sall4, as well as of Suz12, a polycomb family member required for differentiation of pluripotent cells. Thus, DAZL limits both pluripotency and somatic differentiation in nascent PGCs. In addition, we observed that DAZL associates with mRNAs of key Caspases and similarly inhibits their translation. This elegant fail-safe mechanism ensures that, whereas loss of DAZL results in prolonged expression of pluripotency factors, teratoma formation is avoided due to the concomitant activation of the apoptotic cascade. [Display omitted] •DAZL colocalizes with a network of translational inhibitors in granular structures•DAZL interacts with mRNA transcripts of key pluripotency genes and Caspases•Loss of DAZL function leads to prolonged expression of pluripotency genes•Loss of DAZL leads to expression of Caspases, resulting in apoptosis in PGCs In this article, Geijsen and colleagues demonstrate that DAZL acts as a translational suppressor of pluripotency, differentiation, and apoptosis in developing primordial germ cells. As such, DAZL limits pluripotency while simultaneously preventing somatic differentiation and provides an elegant fail-safe mechanism into the PGC system, in which the loss of pluripotency regulation simultaneously triggers germ cell death and prevents germ cell tumor formation.