The transcription factor Runx3 represses the neurotrophin receptor TrkB during lineage commitment of dorsal root ganglion neurons.
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 that 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 Trk-BTrkC double positive neurons differentiate into TrkC single positive neurons.
Inoue
Ken-ichi
K
Institute of Molecular and Cell Biology, Singapore 13 8673.
Ito
Kosei
K
Osato
Motomi
M
Lee
Bernett
B
Bae
Suk-Chul
SC
Ito
Yoshiaki
Y
D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D050677:Core Binding Factor Alpha 3 Subunit / Q000502:physiology*; D004622:Embryo, Mammalian; D005727:Ganglia, Spinal / Q000166:cytology*; D005786:Gene Expression Regulation; D006801:Humans; D009474:Neurons / Q000166:cytology; D051381:Rats; D020813:Receptor, trkB / Q000235:genetics*; D020812:Receptor, trkC / Q000235:genetics; D017475:Receptors, Nerve Growth Factor / Q000235:genetics*
D050677:Core Binding Factor Alpha 3 Subunit; D017475:Receptors, Nerve Growth Factor; D020813:Receptor, trkB; D020812:Receptor, trkC