The transcription factor Runx3 represses the neurotrophin receptor TrkB during lineage commitment of dorsal root ganglion neurons

Authors:
Inoue KI, Ito K, Osato M, Lee B, Bae SC, Ito Y
In:
Source: J Biol Chem
Publication Date: (2007)
Issue: 282(33): 24175-84
Research Area:
Cancer Research/Cell Biology
Neurobiology
Cells used in publication:
Dorsal root gang. (DRG), rat
Species: rat
Tissue Origin: brain
SK-N-DZ
Species: human
Tissue Origin:
TGW
Species: human
Tissue Origin:
LA-N-2
Species: human
Tissue Origin:
SK-N-FI
Species: human
Tissue Origin: bone marrow
Platform:
Nucleofectorâ„¢ I/II/2b
Abstract
Runx3, a Runt-domain transcription factor, determines neurotrophin receptor phenotype in dorsal root ganglion (DRG) neurons. Molecular mechanisms by which Runx3 controls distinct neurotrophin receptors are largely unknown. Here, we show that RUNX3 abolished mRNA induction of TRKB expression, and concomitantly altered the neurotrophin response in a differentiating neuroblastoma cell line. In contrast, RUNX3 did not play a significant role in TRKC regulation even under the relevant BMP signaling pathway. We identified putative regulatory elements of Ntrk2/NTRK2 (a gene which codes for TrkB) using an unbiased computational approach. One of these elements was a highly conserved intronic sequence that contains a cluster of Runx binding sites. In a primary culture of DRG neurons, endogenous Runx3 bound to the consensus cluster, which had repressor activity against the Ntrk2 promoter under the control of NT-3 signaling. Consistent with these findings, Runx3 deficient embryos showed an increased number of trkB+ DRG neurons and failed to maintain trkC expression. Taken together, Runx3 determines TrkC positive sensory neuron identities through the transcriptional repression of TrkB when TrkBTrkC double positive neurons differentiate into TrkC single positive neurons.