Department of Psychiatry, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0603, USA.
Neural Dev. 2010 Jan 22;5:3. doi: 10.1186/1749-8104-5-3.
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.
转录因子 Brn3a 是 pou4f1 基因的产物,在胚胎发生过程中表达于大多数感觉神经元中。先前的研究表明 Brn3a 在早期神经基因的抑制中起作用;在这里,我们描述了 Brn3a 在三叉神经节(TG)中感觉亚型特异性中的第二个主要作用。感觉神经元最初共同表达多种 Trk 家族神经营养素受体,但后来以 TrkA、TrkB 或 TrkC 的独特表达为特征。这些感觉亚型的成熟已知依赖于 Runx 转录因子的表达。新生的 Brn3a 敲除小鼠不能表达 TrkC,后者与 TG 中的机械感受器以及一组与伤害感受器亚型相关的功能性基因相关。在胚胎 Brn3a-/-神经节中,正常的 Runx3 表达从未在 TrkC+神经元中启动,并且在 TrkA+伤害感受器中 Runx1 表达大大减弱。这些变化伴随着异常表达多种 Trks 的神经元中 TrkB 的表达扩大,随后 TrkC 和 TrkA 表达的丧失。在表达 Brn3a-VP16 显性转录激活子的转基因胚胎中,Runx3 mRNA 表达增加,表明它是 Brn3a 的直接调控靶标。染色质免疫沉淀证实 Brn3a 在体内与 Runx3 基因座中组蛋白 H3 乙酰化染色质的保守上游增强子元件结合。这些数据表明 Brn3a 在 Runx 因子的上游起作用,然后抑制 TrkB 表达以允许建立非重叠的 Trk 受体谱并正确分化终末表型。