Brn3a regulates neuronal subtype specification in the trigeminal ganglion by promoting Runx expression during sensory differentiation.
The transcription factor Brn3a, product of the pou4f1 gene, is expressed in most sensory neurons throughout embryogenesis. Prior work has demonstrated a role for Brn3a in the repression of early neurogenic genes; here we describe a second major role for Brn3a in the specification of sensory subtypes in the trigeminal ganglion (TG). Sensory neurons initially co-express multiple Trk-family neurotrophin receptors, but are later marked by the unique expression of TrkA, TrkB or TrkC. Maturation of these sensory subtypes is known to depend on the expression of Runx transcription factors. Newborn Brn3a knockout mice fail to express TrkC, which is associated in the TG with mechanoreceptors, plus a set of functional genes associated with nociceptor subtypes. In embryonic Brn3a-/- ganglia, the normal expression of Runx3 is never initiated in TrkC+ neurons, and Runx1 expression is greatly attenuated in TrkA+ nociceptors. These changes are accompanied by expanded expression of TrkB in neurons that abnormally express multiple Trks, followed by the loss of TrkC and TrkA expression. In transgenic embryos expressing a Brn3a-VP16 dominant transactivator, Runx3 mRNA expression is increased, suggesting that it is a direct regulatory target of Brn3a. Chromatin immunoprecipitation confirms that Brn3a binds in vivo to a conserved upstream enhancer element within histone H3-acetylated chromatin in the Runx3 locus. Together these data show that Brn3a acts upstream of the Runx factors, which then repress TrkB expression to allow establishment of the non-overlapping Trk receptor profiles and correct terminally differentiated phenotypes.
Dykes
Iain M
IM
Department of Psychiatry, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0603, USA.
Lanier
Jason
J
Eng
S Raisa
SR
Turner
Eric E
EE
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics* / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D005455:Fluorescent Antibody Technique; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D005799:Genes, Dominant / Q000235:genetics; D017405:Herpes Simplex Virus Protein Vmw65 / Q000235:genetics / Q000378:metabolism; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism; D020812:Receptor, trkC / Q000235:genetics / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics; D050819:Transcription Factor Brn-3A / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection; D012668:Trigeminal Ganglion / Q000166:cytology* / Q000196:embryology / Q000254:growth & development
D050677:Core Binding Factor Alpha 3 Subunit; D017405:Herpes Simplex Virus Protein Vmw65; D012333:RNA, Messenger; C493730:Runx3 protein, mouse; D015534:Trans-Activators; D050819:Transcription Factor Brn-3A; D020917:Receptor, trkA; D020813:Receptor, trkB; D020812:Receptor, trkC