Two-step regulation of left-right asymmetric expression of Pitx2: initiation by nodal signaling and maintenance by Nkx2.
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.
Shiratori
H
H
Division of Molecular Biology, Institute for Molecular and Cellular Biology, Osaka University, 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan.
Sakuma
R
R
Watanabe
M
M
Hashiguchi
H
H
Mochida
K
K
Sakai
Y
Y
Nishino
J
J
Saijoh
Y
Y
Whitman
M
M
Hamada
H
H
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000502:physiology; D019521:Body Patterning / Q000235:genetics; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000502:physiology; D051858:Forkhead Transcription Factors; D018507:Gene Expression Regulation, Developmental; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D007763:Lac Operon; D055458:Left-Right Determination Factors; D051379:Mice; D008969:Molecular Sequence Data; D055457:Nodal Protein; D009687:Nuclear Proteins; D051761:Paired Box Transcription Factors; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics*; D019076:Transgenes / Q000502:physiology; D014981:Xenopus; D029867:Xenopus Proteins; D000097577:Homeobox Protein PITX2
D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D055458:Left-Right Determination Factors; D055457:Nodal Protein; D009687:Nuclear Proteins; D051761:Paired Box Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins; D000097577:Homeobox Protein PITX2; C102067:FOXH1 protein, Xenopus; C510350:FOXH1 protein, human; C491117:Foxh1 protein, mouse; C526161:LEFTY1 protein, human; C092720:NKX2-5 protein, Xenopus; C095552:NKX2-5 protein, human; C484469:Nkx2-5 protein, mouse; C526008:Nodal protein, mouse; C101485:homeobox protein PITX1; C433629:homeobox protein PITX3