From Dynamic Expression Patterns to Boundary Formation in the Presomitic Mesoderm

The segmentation of the vertebrate body is laid down during early embryogenesis. The formation of signaling gradients, the periodic expression of genes of the Notch-, Fgf- and Wnt-pathways and their interplay in the unsegmented presomitic mesoderm (PSM) precedes the rhythmic budding of nascent somites at its anterior end, which later develops into epithelialized structures, the somites. Although many in silico models describing partial aspects of somitogenesis already exist, simulations of a complete causal chain from gene expression in the growth zone via the interaction of multiple cells to segmentation are rare. Here, we present an enhanced gene regulatory network (GRN) for mice in a simulation program that models the growing PSM by many virtual cells and integrates WNT3A and FGF8 gradient formation, periodic gene expression and Delta/Notch signaling. Assuming Hes7 as core of the somitogenesis clock and LFNG as modulator, we postulate a negative feedback of HES7 on Dll1 leading to an oscillating Dll1 expression as seen in vivo. Furthermore, we are able to simulate the experimentally observed wave of activated NOTCH (NICD) as a result of the interactions in the GRN. We esteem our model as robust for a wide range of parameter values with the Hes7 mRNA and protein decays exerting a strong influence on the core oscillator. Moreover, our model predicts interference between Hes1 and HES7 oscillators when their intrinsic frequencies differ. In conclusion, we have built a comprehensive model of somitogenesis with HES7 as core oscillator that is able to reproduce many experimentally observed data in mice

ICDP workshop on the Lake Tanganyika Scientific Drilling Project: a late Miocene–present record of climate, rifting, and ecosystem evolution from the world's oldest tropical lake

The Neogene and Quaternary are characterized by enormous changes in global climate and environments, including global cooling and the establishment of northern high-latitude glaciers. These changes reshaped global ecosystems, including the emergence of tropical dry forests and savannahs that are found in Africa today, which in turn may have influenced the evolution of humans and their ancestors. However, despite decades of research we lack long, continuous, well-resolved records of tropical climate, ecosystem changes, and surface processes necessary to understand their interactions and influences on evolutionary processes. Lake Tanganyika, Africa, contains the most continuous, long continental climate record from the mid-Miocene (∼10 Ma) to the present anywhere in the tropics and has long been recognized as a top-priority site for scientific drilling. The lake is surrounded by the Miombo woodlands, part of the largest dry tropical biome on Earth. Lake Tanganyika also harbors incredibly diverse endemic biota and an entirely unexplored deep microbial biosphere, and it provides textbook examples of rift segmentation, fault behavior, and associated surface processes. To evaluate the interdisciplinary scientific opportunities that an ICDP drilling program at Lake Tanganyika could offer, more than 70 scientists representing 12 countries and a variety of scientific disciplines met in Dar es Salaam, Tanzania, in June 2019. The team developed key research objectives in basin evolution, source-to-sink sedimentology, organismal evolution, geomicrobiology, paleoclimatology, paleolimnology, terrestrial paleoecology, paleoanthropology, and geochronology to be addressed through scientific drilling on Lake Tanganyika. They also identified drilling targets and strategies, logistical challenges, and education and capacity building programs to be carried out through the project. Participants concluded that a drilling program at Lake Tanganyika would produce the first continuous Miocene–present record from the tropics, transforming our understanding of global environmental change, the environmental context of human origins in Africa, and providing a detailed window into the dynamics, tempo and mode of biological diversification and adaptive radiations.© Author(s) 2020. This open access article is distributed under the Creative Commons Attribution 4.0 License

Reaction scheme of the proposed gene regulatory network (GRN).

<p>The scheme details the full GRN for one cell and part of a neighboring cell for those reactions that involve ligand-receptor interactions like in Delta-Notch signaling or input from the Fgf8 or Wnt3a signal transduction pathways. Color-coded circular areas for each gene symbolize mRNA and protein. For fast changing gene products the transport of mRNA or protein between cytoplasm and nucleus or between cytoplasm and membrane is explicitly simulated, which is indicated by dividing each half-area of the circle again. Regulatory interactions are shown as activating or repressing arrows. Broken lines indicate that the interaction is simulated only in an even more course-grained manner than the other gene regulatory reactions (see <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002586#pcbi.1002586-Tiedemann1" target="_blank">[28]</a> for an extensive discussion). NICD, which originates through cleavage reactions following DLL1 ligand binding to the NOTCH1 receptor <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002586#pcbi.1002586-Fortini1" target="_blank">[3]</a>, was assigned a separate symbol to clarify that only the intracellular domain of the Notch receptor acts in the nucleus as a transcription (co)-factor. The (weak) modulating action of LFNG on D/N signaling is shown as dashed lines - (red for the case of inhibiting action, green for the case of a positive effect on the D/N reaction rate.) Arrows pointing to the symbol for the empty set designate decay reactions of a species. We suppressed them for all species' decays except for those decay rates that we assume as controlled by signal transduction pathways. This applies also to the removal of DLL1 and NOTCH1 from the membrane after their binding, resulting in NOTCH1 cleavage and NICD split-off.</p

Snapshots of virtual expression patterns for <i>Hes7</i> mRNA in simulations of the growing PSM.

<p>The posterior-to-anterior FGF8 gradient is coupled to the HES7 decay. One time step equals 0.1 minute. From left to right shown are the cases of 100% noise added during division of cells in the growth zone of the PSM without (shown also in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003843#pcbi.1003843.s009" target="_blank">movie S3</a>) and with (shown also in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003843#pcbi.1003843.s010" target="_blank">movie S4</a>) D/N cis-inhibition. Snapshots are also displayed for simulation runs wherein the disturbance of oscillator consonance is caused by shutting down the transcription of the core oscillator genes during mitosis. Shown are the cases of 20 min shutdown of the transcription during cell division in the growth zone of the PSM without (shown also in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003843#pcbi.1003843.s012" target="_blank">movie S6</a>) and with (shown also in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003843#pcbi.1003843.s011" target="_blank">movie S5</a>) D/N cis-inhibition. Cells are colored orange in the simulations as long as transcription of their genes is shut down.</p

<i>Mesp2</i> expression without <i>Hes7</i>.

<p>The virtual expression patterns for <i>Mesp2</i> (cytoplasmic mRNA) are shown at five different time points in one complete and part of the following oscillation cycle. Panels on the left show the wild-type situation, panels on the right show <i>Mesp2</i> expression when <i>Hes7</i> is eliminated from the GRN (virtual <i>Hes7</i> knock-out). The tail bud of the PSM is growing from left to right.</p

Virtual expression patterns as simulated <i>in silico</i> by the proposed gene regulatory network.

<p>Expression patterns are shown at three different time points in one oscillation cycle for one half of the PSM. Cytoplasmic mRNAs are colored in blue, proteins in red. The tail bud is growing from left to right. When EPHA4 concentration has reached a certain threshold, the virtual cells change their shape to symbolize epithelialization at the forming somite border.</p

<i>Mesp2</i> expression under reduced Fgf signaling.

<p>Virtual expression patterns for <i>Mesp2</i> (cytoplasmic protein) at five different time points in one complete and part of the following oscillation cycle, when FGF8 protein production rate is reduced by 50%, 600 minutes after the simulation has been started. Panels on the left show the wild-type situation, panels on the right show <i>Mesp2</i> expression when FGF8 signaling was reduced. The tail bud of the PSM is growing from left to right.</p

Synchronization of gene expression in somitogenesis by Delta/Notch cis-inhibition.

<p>Panel <b>A</b> shows our reaction scheme depicting the gene regulatory network. It is sketched for one cell (right) and part of a neighboring cell (left) showing those reactions that involve ligand-receptor interactions in D/N signaling and the <i>Hes7</i> oscillator. Gradient forming genes in the PSM like Fgf8, Wnt3a, and Tbx6 are not shown. Each circular area represents one gene, mRNA and protein are color coded blue and red, respectively. For fast changing gene products we simulate the transport between cellular compartments explicitly, which is indicated by subdivided circle half-areas. Activating or repressing arrows represent regulatory interactions. Degradation or decay reactions are symbolized by arrows to the empty-set symbol. For clarity, we omit in the scheme all species decays except for the D/N cis-interaction, which is assumed to lead to a fast decay of the intracellular D/N complex. Panel <b>B</b> is a sketch showing D/N interactions. D/N-transactivation (lower part of the panel): DLL1 ligand (yellow) on cell 1 binds to NOTCH1 receptor in the membrane of cell 2, whereupon the NOTCH1 intracellular domain is cleaved off, moves into the cell nucleus and activates the <i>Hes7</i> promoter. D/N cis-inhibition (upper part of the panel): We assume an excess of Notch1 in cell 2. DLL1 molecules in the membrane of cell 2 bind NOTCH1 in the same cell and are inactivated after endocytosis to a lysosome. Panel <b>C</b> shows a schematic drawing of the growing PSM: in the anterior region of the PSM (right) cells are synchronized as shown in the blow-up of a small rectangle of the PSM of this region, while in the tail bud cells are not synchronized i.e. out of phase as shown in the blow-up of the left small rectangle. Cells in the blow-ups are coupled by D/N signaling (small yellow and blue bars on the surface of the central cell). Connections are shown only for the central cell.</p

Virtual expression patterns for <i>Hes7</i> mRNA for systems of different dimensionality.

<p>Snapshots are taken at time point 680 min. At the start of the simulation 100% noise was added. The time course of our correlation function is displayed below ending at 50000 time steps equivalent to 5000 min, which shows how the different systems approach the synchronized state (Correlation function = 0). (Abscissa showing time measured in time steps.)</p

Virtual expression patterns for <i>Hes7</i> mRNA in simulation runs with different cis-inhibition values.

<p>Snapshots are taken at 500, 15000, 35000, 50000 time steps (1 time step = 0.1 min) after simulation start for a 7×7×7 cell cube for different D/N cis-inhibition strengths. In all cases 100% noise was added at the start of the simulation. On the left side the time course of the correlation function C(t) (red curve) and the synchronization measure R (blue curve) is shown.(Abscissa showing time measured in time steps.)</p