Gene regulatory logic for reading the Sonic Hedgehog signaling gradient in the vertebrate neural tube

Cell. 2012 Jan 20;148(1-2):273-84. doi: 10.1016/j.cell.2011.10.047.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Eye Proteins / genetics
  • Gene Regulatory Networks*
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neural Stem Cells / metabolism
  • Neural Tube / metabolism*
  • Oligodendrocyte Transcription Factor 2
  • PAX6 Transcription Factor
  • Paired Box Transcription Factors / genetics
  • Repressor Proteins / genetics
  • Signal Transduction*
  • Transcription Factors / metabolism
  • Zebrafish Proteins
  • Zinc Finger Protein Gli3

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Eye Proteins
  • Gli3 protein, mouse
  • Hedgehog Proteins
  • Homeodomain Proteins
  • Kruppel-Like Transcription Factors
  • Nerve Tissue Proteins
  • Nkx2.2 protein
  • Olig2 protein, mouse
  • Oligodendrocyte Transcription Factor 2
  • PAX6 Transcription Factor
  • Paired Box Transcription Factors
  • Pax6 protein, mouse
  • Repressor Proteins
  • Shh protein, mouse
  • Transcription Factors
  • Zebrafish Proteins
  • Zinc Finger Protein Gli3