Pax6 Regulates the Expression of Dkk3 in Murine and Human Cell Lines, and Altered Responses to Wnt Signaling Are Shown in FlpIn-3T3 Cells Stably Expressing Either the Pax6 or the Pax6(5a) Isoform

Forsdahl, Siri; Kiselev, Yury; Hogseth, Rune; Mjelle, Janne Erikke; Mikkola, Ingvild

doi:10.1371/journal.pone.0102559

Cited by 16 publications

(11 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our data also show that Pax6 directly regulates expression of multiple ‘early’ components of Wnt signaling in lens, including Bcl9l, Ccnd1, Dkk3 ( 88 ), Lrp6 and Wnt7a (Figure 8C , D ) consistent with recent data showing that zinc finger-containing protein Bcl9l regulates lens Wnt signaling independent of β-catenin ( 89 ). Pax6 directly regulates expression of 10 genes that can be classified within a broader group of ‘actin-binding, cytoskeleton, filopodia and Wnt signaling’ ( 90 ), including Arhgef7/Pak3bp, Bcl2l11/Bim, Daam1, Hook1, Kank1, Lin7a, Lix1, Palld, Rock1 and Shroom4 (Figure 9D ).…”

Section: Resultssupporting

confidence: 92%

Identification ofin vivoDNA-binding mechanisms of Pax6 and reconstruction of Pax6-dependent gene regulatory networks during forebrain and lens development

et al. 2015

View full text Add to dashboard Cite

The transcription factor Pax6 is comprised of the paired domain (PD) and homeodomain (HD). In the developing forebrain, Pax6 is expressed in ventricular zone precursor cells and in specific subpopulations of neurons; absence of Pax6 results in disrupted cell proliferation and cell fate specification. Pax6 also regulates the entire lens developmental program. To reconstruct Pax6-dependent gene regulatory networks (GRNs), ChIP-seq studies were performed using forebrain and lens chromatin from mice. A total of 3514 (forebrain) and 3723 (lens) Pax6-containing peaks were identified, with ∼70% of them found in both tissues and thereafter called ‘common’ peaks. Analysis of Pax6-bound peaks identified motifs that closely resemble Pax6-PD, Pax6-PD/HD and Pax6-HD established binding sequences. Mapping of H3K4me1, H3K4me3, H3K27ac, H3K27me3 and RNA polymerase II revealed distinct types of tissue-specific enhancers bound by Pax6. Pax6 directly regulates cortical neurogenesis through activation (e.g. Dmrta1 and Ngn2) and repression (e.g. Ascl1, Fezf2, and Gsx2) of transcription factors. In lens, Pax6 directly regulates cell cycle exit via components of FGF (Fgfr2, Prox1 and Ccnd1) and Wnt (Dkk3, Wnt7a, Lrp6, Bcl9l, and Ccnd1) signaling pathways. Collectively, these studies provide genome-wide analysis of Pax6-dependent GRNs in lens and forebrain and establish novel roles of Pax6 in organogenesis.

show abstract

Section: Resultssupporting

confidence: 92%

Identification ofin vivoDNA-binding mechanisms of Pax6 and reconstruction of Pax6-dependent gene regulatory networks during forebrain and lens development

et al. 2015

View full text Add to dashboard Cite

show abstract

“…The overlapping of Wnt6 and Fzd4 might mean that there is a relationship between these two Wnt-signaling genes and that they might be involved in the increased proliferation capacity of Lgr5+ SCs compared to Plp1+ SCs. Unlike other members of the Dickkopf family ( Dkk1 , Dkk2 and Dkk4 ), which inhibit Wnt signaling, Dkk-3 might activate Wnt signaling (Forsdahl et al, 2014 ). The precise mechanism by which Dkk-3 is involved in Wnt signaling remains unclear, and further studies are required to answer this question.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Wnt and Notch-Responsive Lgr5+ Hair Cell Progenitors in the Striolar Region of the Neonatal Mouse Utricle

You

Guo

et al. 2018

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Dysfunctions in hearing and balance are largely connected with hair cell (HC) loss. Although regeneration of HCs in the adult cochlea does not occur, there is still limited capacity for HC regeneration in the mammalian utricle from a distinct population of supporting cells (SCs). In response to HC damage, these Lgr5+ SCs, especially those in the striolar region, can regenerate HCs. In this study, we isolated Lgr5+ SCs and Plp1+ SCs (which originate from the striolar and extrastriolar regions, respectively) from transgenic mice by flow cytometry so as to compare the properties of these two subsets of SCs. We found that the Lgr5+ progenitors had greater proliferation and HC regeneration ability than the Plp1+ SCs and that the Lgr5+ progenitors responded more strongly to Wnt and Notch signaling than Plp1+ SCs. We then compared the gene expression profiles of the two populations by RNA-Seq and identified several genes that were significantly differentially expressed between the two populations, including genes involved in the cell cycle, transcription and cell signaling pathways. Targeting these genes and pathways might be a potential way to activate HC regeneration.

show abstract

“… 70 The primers for OCT4, NANOG, DAZL, AFP, SMA and PAX6 were designed as described previously. 71 , 72 Changes in gene expression were calculated by using the ΔΔCt method.…”

Section: Methodsmentioning

confidence: 99%

Dedifferentiation into blastomere-like cancer stem cells via formation of polyploid giant cancer cells

2017

View full text Add to dashboard Cite

Our recent perplexing findings that polyploid giant cancer cells (PGCCs) acquired embryonic-like stemness and were capable of tumor initiation raised two important unanswered questions: how do PGCCs acquire such stemness, and to which stage of normal development do PGCCs correspond. Intriguingly, formation of giant cells due to failed mitosis/cytokinesis is common in the blastomere stage of the preimplantation embryo. However, the relationship between PGCCs and giant blastomeres has never been studied. Here, we tracked the fate of single PGCCs following paclitaxel-induced mitotic failure. Morphologically, early spheroids derived from PGCCs were indistinguishable from human embryos at the blastomere, polyploid blastomere, compaction, morula and blastocyst-like stages by light, scanning electron or three-dimensional confocal scanning microscopy. Formation of PGCCs was associated with activation of senescence, while budding of daughter cells was associated with senescence escape. PGCCs showed time- and space-dependent activation of expression of the embryonic stem cell markers OCT4, NANOG, SOX2 and SSEA1 and lacked expression of Xist. PGCCs acquired mesenchymal phenotype and were capable of differentiation into all three germ layers in vitro. The embryonic-like stemness of PGCCs was associated with nuclear accumulation of YAP, a key mediator of the Hippo pathway. Spheroids derived from single PGCCs grew into a wide spectrum of human neoplasms, including germ cell tumors, high-grade and low-grade carcinomas and benign tissues. Daughter cells derived from PGCCs showed attenuated capacity for invasion and increased resistance to paclitaxel. We also observed formation of PGCCs and dedifferentiation in ovarian cancer specimens from patients treated with chemotherapy. Taken together, our findings demonstrate that PGCCs represent somatic equivalents of blastomeres, the most primitive cancer stem cells reported to date. Thus, our studies reveal an evolutionarily conserved archaic embryonic program in somatic cells that can be de-repressed for oncogenesis. Our work offers a new paradigm for cancer origin and disease relapse.

show abstract

Pax6 Regulates the Expression of Dkk3 in Murine and Human Cell Lines, and Altered Responses to Wnt Signaling Are Shown in FlpIn-3T3 Cells Stably Expressing Either the Pax6 or the Pax6(5a) Isoform

Cited by 16 publications

References 48 publications

Identification ofin vivoDNA-binding mechanisms of Pax6 and reconstruction of Pax6-dependent gene regulatory networks during forebrain and lens development

Identification ofin vivoDNA-binding mechanisms of Pax6 and reconstruction of Pax6-dependent gene regulatory networks during forebrain and lens development

Characterization of Wnt and Notch-Responsive Lgr5+ Hair Cell Progenitors in the Striolar Region of the Neonatal Mouse Utricle

Dedifferentiation into blastomere-like cancer stem cells via formation of polyploid giant cancer cells

Contact Info

Product

Resources

About