The Pluripotency-Associated Gene<i>Dppa4</i>Is Dispensable for Embryonic Stem Cell Identity and Germ Cell Development but Essential for Embryogenesis

Madan, Babita; Madan, Vikas; Weber, Odile; Tropel, Philippe; Blum, Carmen; Kieffer, Emmanuelle; Viville, Stéphane; Fehling, Hans Jörg

doi:10.1128/mcb.01970-08

Cited by 65 publications

(110 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Of the 53 genes that were higher in PSC derivatives (in red), 22 were also strongly expressed in undifferentiated PSCs relative to somatic cells (indicated with asterisk). This list included LIN28B, DPPA4, and TCF7L1 (TCF3), all of which are known to play a role in ESCs and in very early mammalian development [28,[30][31][32][33]. Furthermore, 35 genes were downregulated in PSC derivatives compared to tissue-derived cells (in green), perhaps reflecting a state of incomplete specification, regardless of the cell type generated.…”

Section: Psc Derivatives and Tissue-derived Counterparts Are Distingumentioning

confidence: 99%

“…OCT4, SOX2, and NANOG were not amongst the 31 probe sets related to pluripotency that remained high in PSC derivatives, demonstrating that these genes were silenced upon differentiation, as has been shown extensively. Instead, most of the 31 probe sets appeared to be not only expressed in PSCs but also play roles in early embryonic development as judged by functional data from lower organisms [27][28][29]. The expression pattern of all genes specifically expressed in PSCs can be found in Supplementary information, Table S1.…”

Section: Psc Derivatives and Tissue-derived Counterparts Are Distingumentioning

confidence: 99%

See 1 more Smart Citation

Defining the nature of human pluripotent stem cell progeny

et al. 2011

View full text Add to dashboard Cite

While it is clear that human pluripotent stem cells (hPSCs) can differentiate to generate a panoply of various cell types, it is unknown how closely in vitro development mirrors that which occurs in vivo. To determine whether human embryonic stem cells (hESCs) and human-induced pluripotent stem cells (hiPSCs) make equivalent progeny, and whether either makes cells that are analogous to tissue-derived cells, we performed comprehensive transcriptome profiling of purified PSC derivatives and their tissue-derived counterparts. Expression profiling demonstrated that hESCs and hiPSCs make nearly identical progeny for the neural, hepatic, and mesenchymal lineages, and an absence of re-expression from exogenous reprogramming factors in hiPSC progeny. However, when compared to a tissuederived counterpart, the progeny of both hESCs and hiPSCs maintained expression of a subset of genes normally associated with early mammalian development, regardless of the type of cell generated. While pluripotent genes (OCT4, SOX2, REX1, and NANOG) appeared to be silenced immediately upon differentiation from hPSCs, genes normally unique to early embryos (LIN28A, LIN28B, DPPA4, and others) were not fully silenced in hPSC derivatives. These data and evidence from expression patterns in early human fetal tissue (3-16 weeks of development) suggest that the differentiated progeny of hPSCs are reflective of very early human development (< 6 weeks). These findings provide support for the idea that hPSCs can serve as useful in vitro models of early human development, but also raise important issues for disease modeling and the clinical application of hPSC derivatives.

show abstract

Section: Psc Derivatives and Tissue-derived Counterparts Are Distingumentioning

confidence: 99%

Section: Psc Derivatives and Tissue-derived Counterparts Are Distingumentioning

confidence: 99%

Defining the nature of human pluripotent stem cell progeny

et al. 2011

View full text Add to dashboard Cite

show abstract

“…However, ECAT15-1 single and ECAT15-1 ECAT15-2 double mutant ESCs showed no significant phenotypes (11). Furthermore, ECAT15-1 deletion in mice did not affect early embryogenesis.…”

mentioning

confidence: 97%

“…Unexpectedly, ECAT15-1 single mutant mice showed perinatal lethality, with deficiency in lung alveolar formation and rib abnormalities (11). Paradoxically, the authors were unable to detect the expression of ECAT15-1 in these organs in wildtype mice by reverse transcription-PCR (RT-PCR) (11).…”

mentioning

confidence: 99%

Essential Roles of ECAT15-2/Dppa2 in Functional Lung Development

Nakamura

Nakagawa

Ichisaka

et al. 2011

Molecular and Cellular Biology

View full text Add to dashboard Cite

Many transcription factors and DNA binding proteins play essential roles in the development of organs in which they are highly and/or specifically expressed. Embryonic stem cell (ESC)-associated transcript 15-1 (ECAT15-1) and ECAT15-2, also known as developmental pluripotency-associated 4 (Dppa4) and Dppa2, respectively, are enriched in mouse ESCs and preimplantation embryos, and their genes encode homologous proteins with a common DNA binding domain known as the SAP motif. Previously, ECAT15-1 was shown to be important in lung development, while it is dispensable in early development. In this study, we generated ECAT15-2 single and ECAT15-1 ECAT15-2 double knockout (double KO) mice and found that almost all mutants, like ECAT15-1 mutants, died around birth with respiratory defects. Paradoxically, the expression of neither ECAT15-1 nor ECAT15-2 was detected in lung organogenesis. Several genes, such as Nkx2-5, Gata4, and Pitx2, were downregulated in the ECAT15-2-null lung. On the other hand, genomic DNA of these genes showed inactive chromatin statuses in ECAT15-2-null ESCs, but not in wild-type ESCs. The chromatin immunoprecipitation (ChIP) assay revealed that ECAT15-2 binds to the regulatory region of Nkx2-5 in ESCs. These data suggest that ECAT15-2 has important roles in lung development, where it is no longer expressed, by leaving epigenetic marks from earlier developmental stages.ECAT15-1 and ECAT15-2 are members of embryonic stem cell (ESC)-associated transcripts (ECATs), which were identified as genes enriched in mouse ESCs by in silico differential display screening (18). The two genes were also known as Dppa4 (developmental pluripotency-associated 4) and Dppa2, respectively, which were identified as novel markers of undifferentiated mouse ESCs with expression patterns similar to Oct3/4 (3).ECAT15-1 and ECAT15-2 are tandemly located on the 16th chromosome in the mouse genome and have similar exonintron structures, encoding polypeptides with 32% identity at the amino acid sequences (13). They contain a common putative DNA binding domain, the SAP motif, which consists of two amphipathic helices separated by an invariant glycine, and have DNA/RNA binding ability and function in chromatin modification (1). ECAT15-1 and ECAT15-2 show a weak homology to another SAP domain-containing protein, PGC7/ Stella/Dppa3 (3), which binds DNA and protects the maternal genome from global demethylation in fertilized eggs (19). Therefore, ECAT15-1 and ECAT15-2 may regulate gene expression through modifying epigenetic status, like Dppa3. Indeed, ECAT15-1 has been shown to associate with chromatin and may therefore play a role in transcriptionally active regions (16).The specific expressions suggest that the two genes play roles in pluripotency and early mouse development. However, ECAT15-1 single and ECAT15-1 ECAT15-2 double mutant ESCs showed no significant phenotypes (11). Furthermore, ECAT15-1 deletion in mice did not affect early embryogenesis. Thus, ECAT15-1 and ECAT15-2 are dispensable in early mouse development and der...

show abstract

“…Notably, Esrrb null embryos survive until 10.5 days post coitum (dpc) and die due to placental abnormalities [73]. Similarly, while Dppa4, Dppa5 and Utf1 are specifically expressed in pluripotent cells in vivo and in culture, the impact of their absence is only observed during late embryonic stages, though redundancy among these genes has not yet been investigated [74][75][76].…”

Section: Regulatory Network For Pluripotency and Lineage Commitment mentioning

confidence: 99%

From blastocyst to gastrula: gene regulatory networks of embryonic stem cells and early mouse embryogenesis

Parfitt

Shen

2014

Phil. Trans. R. Soc. B

View full text Add to dashboard Cite

To date, many regulatory genes and signalling events coordinating mammalian development from blastocyst to gastrulation stages have been identified by mutational analyses and reverse-genetic approaches, typically on a geneby-gene basis. More recent studies have applied bioinformatic approaches to generate regulatory network models of gene interactions on a genome-wide scale. Such models have provided insights into the gene networks regulating pluripotency in embryonic and epiblast stem cells, as well as cell-lineage determination in vivo. Here, we review how regulatory networks constructed for different stem cell types relate to corresponding networks in vivo and provide insights into understanding the molecular regulation of the blastocyst-gastrula transition.

show abstract

The Pluripotency-Associated GeneDppa4Is Dispensable for Embryonic Stem Cell Identity and Germ Cell Development but Essential for Embryogenesis

Cited by 65 publications

References 49 publications

Defining the nature of human pluripotent stem cell progeny

Defining the nature of human pluripotent stem cell progeny

Essential Roles of ECAT15-2/Dppa2 in Functional Lung Development

From blastocyst to gastrula: gene regulatory networks of embryonic stem cells and early mouse embryogenesis

Contact Info

Product

Resources

About