10.002 Patterning is a process that generates spatially non-uniform gene expression patterns or, in a wider sense, Trichostatin A price spatially heterogeneous cellular responses. There are two ways to achieve patterning: one that is spontaneous, resulting from the intrinsic instability of particular reaction diffusion systems, as represented by Turing patterns [1 and 2], another that is more

programmatic, where patterns are generated through the interpretation of morphogen gradients by gene regulatory networks (GRNs), including those involving transcriptional regulation and protein–protein interactions [3, 4 and 5]. In this review, we focus on the mechanisms of the latter – morphogen-dependent programmatic patterning (Figure 1a). The French flag model is a popular classical model for illustrating the concept of patterning (Figure 2a). Partitioning tissues into subregions, a major purpose of patterning, can be achieved by appropriately interpreting given morphogen gradients using GRNs. Each GRN is composed of network motifs that work as functional

units. Theoretical studies have elucidated possible functions of each network motif. Positive feedback loops Proteasome inhibitors in cancer therapy work as switching or thresholding devices by generating bistability in systems (Figure 2b). They also serve a memory function, owing to hysteresis: once the output reaches an ON (or OFF) state, the system maintains the state, even if input levels change somewhat over time [6, 7, 8 and 9]. Negative feedback loops (nFBLs) work as temporal oscillation generators (Figure 2c). Temporal oscillation of gene expression can be converted into traveling waves by appropriate intercellular interaction, such CYTH4 as through Notch-Delta signaling, generating a striped spatial pattern. This mechanism is observed in vertebrate somitogenesis or segmentation in the development of insects with short germ bands [10]. The feed-forward loop (FFL) motif is composed of two signaling pathways with

a common input and a common target gene. Especially when the two pathways have opposite effects on target genes (i.e. activating and inhibiting), the motif is called an incoherent type (iFFL) [11 and 12] (Figure 2d). Its main function is to respond to only the middle range of an input signal. Thus, for a given morphogen gradient, the peak activation of the target gene appears a certain distance away from the source, that is, the iFFL is regarded as a single-stripe generator (Figure 2d). Striped gene expression by the iFFL motif is widely observed in organogenesis [13, 14, 15 and 16]. One of the recent trends in the study on patterning is the quantitative verification of theoretically predicted functions of real GRNs for which wiring structures, reaction parameters, and input-output functions have been determined experimentally [17, 18••, 19•, 20, 21 and 22].