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

• Published in: Cell 2012-01, Vol.148 (1-2), p.273-284
• Main Authors: Balaskas, Nikolaos, Ribeiro, Ana, Panovska, Jasmina, Dessaud, Eric, Sasai, Noriaki, Page, Karen M., Briscoe, James, Ribes, Vanessa
• Format: Article
• Language: English
• Subjects: Animals; Basic Helix-Loop-Helix Transcription Factors - genetics; cell differentiation; Differentiation; Eye Proteins - genetics; Gene expression; Gene Regulatory Networks; Hedgehog protein; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Language; Mice; Mice, Transgenic; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neural Stem Cells - metabolism; Neural tube; Neural Tube - metabolism; Oligodendrocyte Transcription Factor 2; Paired Box Transcription Factors - genetics; Pattern formation; PAX6 Transcription Factor; regulator genes; Repressor Proteins - genetics; Signal Transduction; tissues; transcription (genetics); Transcription factors; Transcription Factors - metabolism; Zinc Finger Protein Gli3
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2011.10.047

Secreted 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. [Display omitted] ► Shh morphogen produces a dynamic gradient of Gli activity in the neural tube ► The dynamics of Gli activity are interpreted by a downstream transcriptional network ► The regulatory logic of the network explains both spatial and temporal gene responses ► The network confers hysteresis and robustness to fluctuations in signaling The vertebrate neural tube is patterned by a Sonic Hedgehog signaling network consisting of three transcription factors. The design of this network confers memory to the signal and robustness to fluctuations in signal intensity, revealing that morphogen interpretation is an emergent property of network architecture.