Two-step regulation of left-right asymmetric expression of Pitx2: initiation by nodal signaling and maintenance by Nkx2

Mol Cell. 2001 Jan;7(1):137-49. doi: 10.1016/s1097-2765(01)00162-9.

Abstract

Pitx2 is left--right (L--R) asymmetrically expressed initially in the lateral plate and later in primordial visceral organs. The transcriptional regulatory mechanisms that underlie L--R asymmetric expression of Pitx2 were investigated. Mouse Pitx2 has a left side-specific enhancer (ASE) that mediates both the initiation and maintenance of L--R asymmetric expression. This element contains three binding sites for the transcription factor FAST. The FAST binding sites function as Nodal-responsive elements and are sufficient for the initiation but not for the maintenance of asymmetric expression. The maintenance requires an Nkx2-5 binding site also present within the ASE. These results suggest that the left-sided expression of Pitx2 is directly initiated by Nodal signaling and is subsequently maintained by Nkx2. Such two-step control may represent a general mechanism for gene regulation during development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Binding Sites / physiology
  • Body Patterning / genetics
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Enhancer Elements, Genetic / physiology
  • Forkhead Transcription Factors
  • Gene Expression Regulation, Developmental*
  • Homeobox Protein Nkx-2.5
  • Homeodomain Proteins / chemistry
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Lac Operon
  • Left-Right Determination Factors
  • Mice
  • Molecular Sequence Data
  • Nodal Protein
  • Nuclear Proteins*
  • Paired Box Transcription Factors
  • Signal Transduction / genetics
  • Transcription Factors / chemistry
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transforming Growth Factor beta / genetics*
  • Transgenes / physiology
  • Xenopus
  • Xenopus Proteins*

Substances

  • DNA-Binding Proteins
  • FOXH1 protein, Xenopus
  • FOXH1 protein, human
  • Forkhead Transcription Factors
  • Foxh1 protein, mouse
  • Homeobox Protein Nkx-2.5
  • Homeodomain Proteins
  • LEFTY1 protein, human
  • Left-Right Determination Factors
  • NKX2-5 protein, Xenopus
  • NKX2-5 protein, human
  • Nkx2-5 protein, mouse
  • Nodal Protein
  • Nodal protein, mouse
  • Nuclear Proteins
  • Paired Box Transcription Factors
  • Transcription Factors
  • Transforming Growth Factor beta
  • Xenopus Proteins
  • homeobox protein PITX1
  • homeobox protein PITX3
  • homeobox protein PITX2