A direct role of the homeodomain proteins Phox2a/2b in noradrenaline neurotransmitter identity determination

Hyemyung Seo, Seok Jong Hong, Su Guo, Hee Sun Kim, Chun Hyung Kim, Dong Youn Hwang, Ole Isacson, Arnon Rosenthal, Kwang Soo Kim*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

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 β-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.

Original languageEnglish (US)
Pages (from-to)905-916
Number of pages12
JournalJournal of neurochemistry
Volume80
Issue number5
DOIs
StatePublished - 2002

Keywords

  • Dopamine
  • Neurotransmitter
  • Noradrenergic neuron
  • Noradrenergic phenotype
  • Phox2a
  • Ranscription
  • β-hydroxylase

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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