A gene regulatory motif that generates oscillatory or multiway switch outputs

Abstract

The pattern of gene expression in a developing tissue determines the spatial organization of cell type generation. We previously defined regulatory interactions between a set of transcription factors that specify the pattern of gene expression in progenitors of different neuronal subtypes of the vertebrate neural tube. These transcription factors form a circuit that acts as a multistate switch, patterning the tissue in response to a gradient of Sonic Hedgehog. Here, by simplifying aspects of the regulatory interactions, we found that the topology of the circuit allows either switch-like or oscillatory behaviour depending on parameter values. The qualitative dynamics appear to be controlled by a simpler sub-circuit, which we term the AC–DC motif. We argue that its topology provides a natural way to implement a multistate gene expression switch and we show that the circuit is readily extendable to produce more distinct stripes of gene expression. Our analysis also suggests that AC–DC motifs could be deployed in tissues patterned by oscillatory mechanisms, thus blurring the distinction between pattern-formation mechanisms relying on temporal oscillations or graded signals. Furthermore, during evolution, mechanisms of gradient interpretation might have arisen from oscillatory circuits, or vice versa.

A spectrum of modularity in multi‐functional gene circuits

“…Importantly, these results go a step further than previous studies where the overlap between functional modules is only partial (Fig A–C). Second, in contrast to previous studies which focused on particular gene circuit architectures able to perform multiple functions [where these functions range from distinct dynamical behaviors (Panovska‐Griffiths et al , ), to different single cell fates (Martin & Wagner, ) or distinct patterning functions (Palau‐Ortin et al , )], here our exhaustive theoretical search of circuit space was less biased and thus leads to more universal conclusions.…”

“… AIn order to achieve multiple functions it has been proposed that circuits can be structurally modular , i.e they allocate distinct highly interconnected and non‐overlapping sets of genes to each individual function (Di Ferdinando et al , ; Solé & Valverde, ; Clune et al , ; Ellefsen et al , ). In this scenario modules do not overlap. B, CPartial module overlap (Panovska‐Griffiths et al , ; Sorrells et al , ). The AC/DC circuit is able to alternate between distinct behaviors upon a change in the strength of its gene interactions.…”

Speed regulation of genetic cascades allows for evolvability in the body plan specification of insects

“…In this model, an arrest front sweeps the tissue and freezes oscillations of a molecular clock into stripes. The "spatial and temporal gradient" model exemplifies the latter, which was proposed in the context of vertebrate neural tube development (15,(17)(18)(19). In this model, the concentration of and exposure time to a more or less static (nonretracting) gradient regulates the sequential activation of genes.…”

Polarization and migration in the zebrafish posterior lateral line system

“…We typically take n = m = 5, which slightly increases the regime of bistability of the system compared to the case n , m ≈ 2, but similar behavior is obtained for n ≠ m and for smaller values of these Hill coefficients. The limit n → ∞ leads to analytic insights, as noted in [17]. In brief, negative feedback is proportional to decreasing Hill functions of the form where c is a dimensionless quantity (ratio of bound receptor level to IC 50 parameter).…”