PUBLICATION
A direct role of the homeodomain proteins Phox2a/2b in noradrenaline neurotransmitter identity determination
- Authors
- Seo, H. Hong, S.J., Guo, S., Kim, H.S., Kim, C.H., Hwang, D.Y., Isacson, O., Rosenthal, A., and Kim, K.S.
- ID
- ZDB-PUB-020513-2
- Date
- 2002
- Source
- Journal of neurochemistry 80(5): 905-916 (Journal)
- Registered Authors
- Guo, Su, Seo, Hee-Chan
- Keywords
- none
- MeSH Terms
-
- 5' Untranslated Regions/physiology
- Animals
- Binding Sites/physiology
- Brain/embryology
- Brain/metabolism*
- Cell Differentiation
- Dimerization
- Dopamine beta-Hydroxylase/genetics
- Dopamine beta-Hydroxylase/metabolism
- Gene Expression/drug effects
- Gene Expression/physiology
- Homeodomain Proteins/antagonists & inhibitors
- Homeodomain Proteins/genetics
- Homeodomain Proteins/metabolism*
- Humans
- Mutagenesis, Site-Directed
- Nerve Tissue Proteins
- Neurons/drug effects
- Neurons/metabolism*
- Norepinephrine/metabolism*
- Oligonucleotides, Antisense/pharmacology
- Promoter Regions, Genetic/drug effects
- Protein Binding/physiology
- Rats
- Regulatory Sequences, Nucleic Acid/physiology
- Structure-Activity Relationship
- Transcription Factors/antagonists & inhibitors
- Transcription Factors/genetics
- Transcription Factors/metabolism*
- Transcriptional Activation/drug effects
- Transfection
- Zebrafish
- PubMed
- 11948255 Full text @ J. Neurochem.
Citation
Seo, H. Hong, S.J., Guo, S., Kim, H.S., Kim, C.H., Hwang, D.Y., Isacson, O., Rosenthal, A., and Kim, K.S. (2002) A direct role of the homeodomain proteins Phox2a/2b in noradrenaline neurotransmitter identity determination. Journal of neurochemistry. 80(5):905-916.
Abstract
Development of noraderenergic (NA) neurons in the vertebrate brain is dependent on the homeodomain proteins Phox2a and 2b. Here, we show that Phox2a directly controls the NA identity by activating NA-synthesizing dopamine beta-hydroxylase (DBH ) gene. Single point mutations in the homeodomain of Phox2a resulted in a failure to transactivate the DBH promoter in vitro and resulted in the loss of NA neurons in vivo. In addition, injection of Phox2a-specific antisense oligonucleotide induced the loss of NA neurons in developing zebrafish. Phox2a and 2b activate the DBH promoter and bind to three domains (PBD1-3). PBD1 is composed of two overlapping sites with which monomers of Phox2a can interact. In contrast, PBD2 and 3 interact with the dimeric form of Phox2a. Mutations in three or four, but not one or two, of the binding sites completely abolished activation of the DBH promoter by Phox2a or 2b, while the conversion of PBD3 to a consensus motif (ATTA) improved the DBH promoter activity by > 10-fold. Taken together, these findings establish that Phox2a and 2b control the development of NA neurons in part by directly transactivating DBH transcription through interactions with four binding sites clustered in the proximal promoter.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping