Vertebrate Cell Differentiation, Evolution, and Diseases: The Vertebrate-Specific Developmental Potential Guardians VENTX/NANOG and POU5/OCT4 Enter the Stage

Abstract

During vertebrate development, embryonic cells pass through a continuum of transitory pluripotent states that precede multi-lineage commitment and morphogenesis. Such states are referred to as “refractory/naïve” and “competent/formative” pluripotency. The molecular mechanisms maintaining refractory pluripotency or driving the transition to competent pluripotency, as well as the cues regulating multi-lineage commitment, are evolutionarily conserved. Vertebrate-specific “Developmental Potential Guardians” (vsDPGs; i.e., VENTX/NANOG, POU5/OCT4), together with MEK1 (MAP2K1), coordinate the pluripotency continuum, competence for multi-lineage commitment and morphogenesis in vivo. During neurulation, vsDPGs empower ectodermal cells of the neuro-epithelial border (NEB) with multipotency and ectomesenchyme potential through an “endogenous reprogramming” process, giving rise to the neural crest cells (NCCs). Furthermore, vsDPGs are expressed in undifferentiated-bipotent neuro-mesodermal progenitor cells (NMPs), which participate in posterior axis elongation and growth. Finally, vsDPGs are involved in carcinogenesis, whereby they confer selective advantage to cancer stem cells (CSCs) and therapeutic resistance. Intriguingly, the heterogenous distribution of vsDPGs in these cell types impact on cellular potential and features. Here, we summarize the findings about the role of vsDPGs during vertebrate development and their selective advantage in evolution. Our aim to present a holistic view regarding vsDPGs as facilitators of both cell plasticity/adaptability and morphological innovation/variation. Moreover, vsDPGs may also be at the heart of carcinogenesis by allowing malignant cells to escape from physiological constraints and surveillance mechanisms.

In vivo targeted and deterministic single cell malignant transformation

“…The robust deterministic process of single-cell cancer induction that we uncovered suggests that the aberrant reactivation of Epi-Driver genes involved in reprogramming/pluripotency (such as VENTX/NANOG, POU5/OCT4) might be relevant to the irreversible malignant transformation of a cell. Reprogramming Epi-Drivers are important regulators of cell viability, survival and proliferation in several cellular contexts, from embryonic stem cells to cancer cells [22][23][24][25][26][27] . Due to their capacity to modulate epigenetic memory and cell plasticity, these reprogramming factors may drive the early stages of malignant transformation in vivo once (re)activated aberrantly.…”

“…Due to their capacity to modulate epigenetic memory and cell plasticity, these reprogramming factors may drive the early stages of malignant transformation in vivo once (re)activated aberrantly. They likely share some mechanism(s) with processes such as induced nuclear-reprogramming 22,23,24 , pluripotency maintenance and/or endogenous cell reprogramming during development 37 . Thus, consistent with our results, the reactivation 37 of the Neural Crest (NC) Progenitor program (possibly via the stochastic expression of VENTX/NANOG and/or POU5/OCT4) has been shown in BRAF/p53 double mutant cells to yield NC-related tumors in vivo [30][31][32] .…”

“…Recently, it has been shown that genes involved in embryonic development, pluri/multipotency and cell reprogramming such as VENTX/NANOG and POU5/OCT4 are abnormally reactivated in late cancer stages, where acting as Epigenetic Drivers (Epi-Drivers) they empower cancer cells with Cancer Stem Cell (CSCs) features, resistance to anti-cancer therapies and potential for cancer recurrence/relapse 21,22,23,24,25,26,27 . Although it is evident that such Epi-Drivers confer a selective advantage to CSCs in a full-blown cancer, whether they play a role during the early phases of malignant transformation is still unknown.…”

“…Since both kRasG12V and Ventx have been reported to play a role in brain cancer 12,13 , we decided to activate the oncogene kRasG12V at 1dpf in a single normal cell of the brain of a transgenic zebrafish (injected with the mRNA of Ventx-GR at 1 cell stage). Activation of the oncogene in a single cell was achieved by illumination at 405nm to uncage cCyc in a small region (diameter ~80 m) of the brain (in the vicinity of the otic vesicle) (Fig.…”

The Development and Application of Opto-Chemical Tools in the Zebrafish

“…Large-scale phenotypic screening after mutagenesis has been performed owing to the high fertility and fecundity of zebrafish, revealing thousands of mutations involved in embryonic development [ 199 , 200 ]. In another excellent example, zebrafish have been extensively used to study vertebrate somitogenesis which requires spatiotemporal integration of multiple signaling systems such as the fibroblast growth factor (FGF), transforming growth factor β (TGF-β), pluripotency factors (e.g., VENTX/NANOG), and Notch and Wnt signaling during anteroposterior axis elongation, cell fate choice and tissue morphogenesis [ 201 , 202 , 203 ]. Evidently, cellular signaling pathways are highly coordinated during development, acting precisely at specific times and in specific regions in the embryos.…”