Integration of anteroposterior and dorsoventral regulation of Phox2b transcription in cranial motoneuron progenitors by homeodomain proteins.
Little is known about the molecular mechanisms that integrate anteroposterior (AP) and dorsoventral (DV) positional information in neural progenitors that specify distinct neuronal types within the vertebrate neural tube. We have previously shown that in ventral rhombomere (r)4 of Hoxb1 and Hoxb2 mutant mouse embryos, Phox2b expression is not properly maintained in the visceral motoneuron progenitor domain (pMNv), resulting in a switch to serotonergic fate. Here, we show that Phox2b is a direct target of Hoxb1 and Hoxb2. We found a highly conserved Phox2b proximal enhancer that mediates rhombomere-restricted expression and contains separate Pbx-Hox (PH) and Prep/Meis (P/M) binding sites. We further show that both the PH and P/M sites are essential for Hox-Pbx-Prep ternary complex formation and regulation of the Phox2b enhancer activity in ventral r4. Moreover, the DV factor Nkx2.2 enhances Hox-mediated transactivation via a derepression mechanism. Finally, we show that induction of ectopic Phox2b-expressing visceral motoneurons in the chick hindbrain requires the combined activities of Hox and Nkx2 homeodomain proteins. This study takes an important first step to understand how activators and repressors, induced along the AP and DV axes in response to signaling pathways, interact to regulate specific target gene promoters, leading to neuronal fate specification in the appropriate developmental context.
Samad
Omar Abdel
OA
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR7104, BP 10142-67404 Illkirch Cedex, CU de Strasbourg, France.
Geisen
Marc J
MJ
Caronia
Giuliana
G
Varlet
Isabelle
I
Zappavigna
Vincenzo
V
Ericson
Johan
J
Goridis
Christo
C
Rijli
Filippo M
FM
D000818:Animals; D001483:Base Sequence; D019521:Body Patterning / Q000235:genetics / Q000502:physiology*; D002642:Chick Embryo; D004742:Enhancer Elements, Genetic; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000502:physiology*; D012249:Rhombencephalon / Q000196:embryology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; C109220:NBPhox protein; C000715627:Nkx2-2 protein, mouse; D014157:Transcription Factors