title: Gene regulatory logic for reading the Sonic Hedgehog signaling gradient in the vertebrate neural tube.
abstract: 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.
authors.affiliation: Developmental Biology, National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Balaskas
authors.forename: Ana
authors.initials: A
authors.lastname: Ribeiro
authors.forename: Jasmina
authors.initials: J
authors.lastname: Panovska
authors.forename: Eric
authors.initials: E
authors.lastname: Dessaud
authors.forename: Noriaki
authors.initials: N
authors.lastname: Sasai
authors.forename: Karen M
authors.initials: KM
authors.lastname: Page
authors.forename: James
authors.initials: J
authors.lastname: Briscoe
authors.forename: Vanessa
authors.initials: V
authors.lastname: Ribes
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics; D053263:Gene Regulatory Networks; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000378:metabolism; D054259:Neural Tube / Q000378:metabolism*; D000076104:Oligodendrocyte Transcription Factor 2; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D029961:Zebrafish Proteins; D000074290:Zinc Finger Protein Gli3
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005136:Eye Proteins; D053823:Hedgehog Proteins; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins; D014157:Transcription Factors; D029961:Zebrafish Proteins; D000074290:Zinc Finger Protein Gli3; C465571:Gli3 protein, mouse; C512773:Olig2 protein, mouse; C000605732:Pax6 protein, mouse; C465570:Shh protein, mouse