Gene Regulatory Logic for Reading the Sonic Hedgehog Signaling Gradient in the Vertebrate Neural Tube

Abstract

SummarySecreted signals, known as morphogens, provide the positional information that organizes gene expression and cellular differentiation in many developing tissues. In the vertebrate neural tube, Sonic Hedgehog (Shh) acts as a morphogen to control the pattern of neuronal subtype specification. Using an in vivo reporter of Shh signaling, mouse genetics, and systems modeling, we show that a spatially and temporally changing gradient of Shh signaling is interpreted by the regulatory logic of a downstream transcriptional network. The design of the network, which links three transcription factors to Shh signaling, is responsible for differential spatial and temporal gene expression. In addition, the network renders cells insensitive to fluctuations in signaling and confers hysteresis—memory of the signal. Our findings reveal that morphogen interpretation is an emergent property of the architecture of a transcriptional network that provides robustness and reliability to tissue patterning.

Essential role for ligand-dependent feedback antagonism of vertebrate hedgehog signaling by PTCH1, PTCH2 and HHIP1 during neural patterning

“…The floorplate, as demarcated by the highest levels of FOXA2 and SHH synthesis, extends to the dorsal limits of the latter, but only to mid-regions of the neural tube in the former. This may reflect the importance of timing in HHdependent patterning (Balaskas et al, 2012;Dessaud et al, 2008;Dessaud et al, 2007). In Ptch1 −/− embryos, ectopic signaling occurs once cells gain competence to initiate a HH response.…”

“…This initial pattern established by SHH ligand is thought to be inherently disorganized and must be refined by cross-repressive interactions between transcription factors expressed in neighboring domains, resulting in sharp boundaries between neural progenitor populations (Briscoe et al, 1999;Briscoe et al, 2000;Ericson et al, 1997). In fact, mathematical models of the downstream gene regulatory network (GRN) initiated by HH signaling can recapitulate the graded and discrete patterns established in the ventral neural tube independent of threshold responses to HH ligand (Balaskas et al, 2012). This suggests that precise interpretation of a SHH gradient is not required to establish distinct progenitor domains in the ventral neural tube (Balaskas et al, 2012).…”

“…In fact, mathematical models of the downstream gene regulatory network (GRN) initiated by HH signaling can recapitulate the graded and discrete patterns established in the ventral neural tube independent of threshold responses to HH ligand (Balaskas et al, 2012). This suggests that precise interpretation of a SHH gradient is not required to establish distinct progenitor domains in the ventral neural tube (Balaskas et al, 2012). However, our observation of significant mixing of pV3 and pMN populations in embryos with compromised LDA demonstrates the importance of feedback inhibition at the level of HH ligand to produce sharp boundaries between progenitor populations and suggests that the downstream GRN is not sufficient to properly pattern the ventral neural tube in the context of deregulated HH ligand.…”

Roles for Hedgehog signaling in adult organ homeostasis and repair

“…However, PTCH1 production is upregulated with increasing HH levels, thus forming a negative-feedback loop in the canonical signaling pathway (Ribes and Briscoe, 2009). Recent analysis of the cis-regulatory modules of HH-regulated genes has revealed that cells interpret the levels of HH signaling through differential affinity GLI-binding sites in target genes, whereas tissue specificity is achieved through the participation of co-activators (Balaskas et al, 2012;Oosterveen et al, 2012Oosterveen et al, , 2013. Although the required receptors PTCH1/PTCH2 and SMO are committed to propagating canonical HH signaling, in some processes pathway activation does not result in GLI-induced transcriptional changes and this is referred to as non-canonical HH signaling (Brennan et al, 2012;Briscoe and Therond, 2013;Jenkins, 2009) (see Box 1).…”

Application of a systems approach to study developmental gene regulation

“…Therefore, the study of interaction between GRNs from neighboring cell types may potentially lead to many new discoveries in cell development. Similar systems biology approaches have been applied to study other developing tissues or organs, such as the vertebrate neural tube (Balaskas et al 2012), limb bud (Bénazet et al 2009), and hematopoietic cells (Kirouac et al 2009(Kirouac et al , 2010). …”