By using oscillating micro-magnets, Mechanics and Genetics of Embryonic and Tumoral Development group (CNRS/Institut Curie) mimicked the cell pulsations of the mesoderm, in a mutant defective in pulsations that does not gastrulate anymore. This rescued its gastrulation in the early Drosophila embryo, namely triggered the process that initiates embryonic morphogenesis of all animal organisms (Fig. 1).
The use of such magnetic tool, for which forces is of purely physical origin with physiological amplitude and frequency, demonstrates that active gastrulation is triggered by the mechanical constraints generated by preceding cell pulsations. This acts through the activation of a Fog mechanosensitive signalling pathway known to induce the Rho dependent apical stabilisations of Myo-II that generates mesoderm invagination.
At the origin of our own embryonic development, humans share with all animal organisms the critical step that initiates embryonic morphogenesis from deepest times, i.e more than 800 millions years ago: gastrulation.
Gastrulation consists in the formation of large domains of tissue that internalize into the early embryo often like tubes, and which will develop as the internal organs of the adult animal, like the digestive tracks, or the heart, muscles and the kidney lung for most complex animals.
In the Drosophila embryo, the first tube to form is the mesoderm, from which will derive all internal organs of the adult organism, except the digestive track. It forms thanks to the apical stabilisation of the molecular motor Myo-II at the external embryonic surface of the cell, which has the function of constricting the external surface of the embryonic tissue, thereby inducting the inward curvature of the tissue leading to the internalisation of the mesodermal tube.
This constriction follows two phases. During the first phase, cells constrict in an erratic and unstable way, due to the erratic and unstable formation of Myo-II spots at the mesoderm cells apexes. Then, cells constrict in a stable and coordinated way, due to the stabilisation of the Myo-II spots progressively reaching cell apexes.
The group demonstrated that the mechanical constraints developed by the stochastic fluctuations of shape of the apexes activate the apical stabilisation of Myo-II, thereby triggering the active process of mesoderm invagination.
To do so, the team used a mutant in which mesodermal cells do not fluctuate anymore, and which does not show any mesoderm invagination. Apex shape fluctuations have been mimicked with the amplitude of 500 nm only, by magnetic means. Effectively, magnetic liposomes have been injected inside mesodermal cells and have approached at a few microns a network of micro-magnets which individual size, of 10 microns, is on the order of magnitude of the individual cell size. The specificity of the local magnetic field produced by these magnets was to vary with time, controlled by the experimentalist, so that we made oscillate the local micrometric magnetic fields in such a way cells apex began to pulsate exactly like in the non mutated embryo (Fig. 2-left). In response to this stimulation, the stabilisation of Myo-II and the trigger of mesoderm invagination have been observed (Fig.2-right). This stimulation is due to a mechanical activation of biochemical reactions, which we have identified as the activation of the Fog signalling pathway. (Fig.1)
In addition, the team has shown, by magnetic means again, that the mechanical deformation, this time induced by the mesoderm invagination on the cells of the endoderm of the posterior pole of the embryo (the future embryonic posterior gut track), triggers the apical stabilisation of Myo-II and initiate the posterior gut track formation through a similar mechanotransductive Fog dependent process (Fig. 3).
This demonstrates that the trigger of gastrulation, which consists in the first morphogenetic movements initiating embryogenesis of all of the animal organisms from deepest times, is mechanically induced, in the Drosophila embryo, which embryogenesis biochemical regulation is the best the characterized of animal kingdom, by an active process of mechanical trigger of apical stabilisation of Myo-II generating the invagination of both the endoderm and the mesoderm.
The gastrulating embryo, with apex pulsations, before Myo-II apical accumulation (in red) leading to cell constriction and invagination (cell membranes in green).
In a mutant of snail in which cell apex pulsations are strongly reduced before gastrulation, no apical accumulation of Myo-II and mesoderm invagination is observed.
In a mutant of snail in which a network of micromagnets (in black) generates apex size fluctuations in mesoderm cells loaded with magnetic liposomes, both the apical accumulation of Myo-II and apical constriction are rescued, leading to mesoderm invagination. Please note the degradation of the image resolution due to the pdms substrate of the magnet.