In the early vertebrate embryo, cells are born in a pluripotent state before progressively committing to multiple lineages within the three germ-layers, ectoderm, mesoderm, and endoderm. A proper balance between pluripotency and commitment is needed to ensure correct development. Laurent Kodjabachian’s team in IBDM reveals a new mechanism that maintains this balance. This study has been published on June 27 2017 in eLife.

Pluripotency refers to the capacity of embryonic cells to take part to all lineages that compose the body (nervous system, skin, muscles etc…) depending on the signals that they receive. This property must be tightly controlled to allow progressive and correct development of the embryo. If cells remain pluripotent too long, development is stalled; if instead cells engage too fast, certain territories fail to form. Thus, understanding the basis of the transition between pluripotency and commitment is crucial in developmental and stem cell biology.

The mechanisms underlying pluripotency have mostly been studied in vitro through culture of mouse or human embryonic stem cells. These studies have revealed that pluripotency is sustained by a network of transcription factors, among which Nanog is a key player. When this network is turned off, cells become competent to commit to various lineages. It is known that MEK1, an upstream kinase in the MAPK pathway, promotes the transition between the pluripotent and competent states of embryonic cells.

Scerbo and colleagues have used the embryo of the amphibian Xenopus to study the mode of action of MEK1 in vivo. MEK1 depletion prevents embryonic development; cells remain blocked in a pluripotent state and are unable to respond to differentiation cues. The Xenopus genus has lost Nanog, but its function is carried out by its close relative Ventx (Scerbo et al., 2012). Under normal conditions, Ventx protein is progressively eliminated, and its extinction at the end of gastulation marks the end of the pluripotency phase. In absence of MEK1 activity, Ventx is no longer degraded, but development can be restored when MEK1 and Ventx are concomitantly inhibited. Thus, the MEK1/Ventx axis lies at the heart of the pluripotency to commitment transition (Figure 1).

The surprise came when the distribution of Ventx protein was analysed by fluorescent immunohistochemistry. Under normal conditions, a significant fraction of dividing pluripotent cells displayed unequal partitioning of Ventx between the two daughter nuclei (Figure 2A). In contrast, in absence of MEK1 activity, divisions became symmetrical and the two daughter nuclei inherited similar amounts of Ventx protein (Figure 2B). This mechanism of asymmetric distribution of Ventx during mitosis could allow to maintain the pool of pluripotent cells, while progressively delivering founder cells to build up primitive embryonic tissues. It remains to determine how MEK1 controls the asymmetric distribution of Ventx.

Is this mechanism restricted to Xenopus or is it commun to all vertebrates? Rodents have lost Ventx, but Nanog could be subjected to the same regulation, which can easily be tested in mouse. In contrast, both Nanog and Ventx are present in human and expressed in embryonic stem cells, as well as cancer stem cells. On the basis of studies in Xenopus, it will be interesting to evaluate the implication of Ventx in pluripotency in human, and its potential regulation by MEK1, a question of potential importance in the field of cancer research.

Scerbo P. et al. PLoS One. 7(5):e36855. 2012.

Figure 1

Figure 1: The transition between pluripotency and commitment is controlled by MEK1-mediated clearance of Ventx.
© Pierluigi Scerbo

Figure 2. Asymmetric distribution of Ventx protein during mitosis. A. In a control embryo, Ventx protein (magenta) is unequally distributed between the two daughter nuclei (blue) during division of pluripotent cells. Two adjacent dividing cells can be seen in this photograph. B. A form of Ventx, which resists degradation induced by MEK1, is equally distributed between the two daughter nuclei. Cell membranes were visualized through GFP expression. © Laurent Kodjabachian

Figure 2. Asymmetric distribution of Ventx protein during mitosis.
A. In a control embryo, Ventx protein (magenta) is unequally distributed between the two daughter nuclei (blue) during division of pluripotent cells. Two adjacent dividing cells can be seen in this photograph. B. A form of Ventx, which resists degradation induced by MEK1, is equally distributed between the two daughter nuclei. Cell membranes were visualized through GFP expression.
© Laurent Kodjabachian

To know more
Lineage commitment of embryonic cells involves MEK1-dependent clearance of pluripotency regulator Ventx2.
Pierluigi Scerbo, Leslie Marchal and Laurent Kodjabachian.

Contact : Laurent.kodjabachian@univ-amu.fr