Liu Yang, Yang Fu-Chia, Okuda Tsukasa, Dong Xinzhong, Zylka Mark J, Chen Chih-Li, Anderson David J, Kuner Rohini, Ma Qiufu
Dana-Farber Cancer Institute and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Neurosci. 2008 Jan 2;28(1):125-32. doi: 10.1523/JNEUROSCI.4472-07.2008.
Mrg class G-protein-coupled receptors (GPCRs) are expressed exclusively in sensory neurons in the trigeminal and dorsal root ganglia. Pharmacological activation of Mrg proteins is capable of modulating sensory neuron activities and elicits nociceptive effects. In this study, we illustrate a control mechanism that allows the Runx1 runt domain transcription factor to generate compartmentalized expression of these sensory GPCRs. Expression of MrgA, MrgB, and MrgC subclasses is confined to an "A/B/C" neuronal compartment that expresses Runx1 transiently (or does not express Runx1), whereas MrgD expression is restricted to a "D" compartment with persistent Runx1 expression. Runx1 is initially required for the expression of all Mrg genes. However, during late development Runx1 becomes a repressor for MrgA/B/C genes. As a result, MrgA/B/C expression persists only in the Runx1- "A/B/C" compartment. In delta446 mice, in which Runx1 lacks the C-terminal repression domain, expression of MrgA/B/C genes is dramatically expanded into the Runx1+ "D" compartment. MrgD expression, however, is resistant to Runx1-mediated repression in the "D" compartment. Therefore, the creation of Runx1+ and Runx1- compartments, in conjunction with different responses of Mrg genes to Runx1-mediated repression, results in the compartmentalized expression of MrgA/B/C versus MrgD genes. Within the MrgA/B/C compartment, MrgB4-expressing neurons innervate exclusively the hairy skin. Here we found that Smad4, a downstream component of bone morphological protein-mediated signaling, is required selectively for the expression of MrgB4. Our study suggests a new line of evidence that specification of sensory subtypes is established progressively during perinatal and postnatal development.
Mrg类G蛋白偶联受体(GPCRs)仅在三叉神经节和背根神经节的感觉神经元中表达。Mrg蛋白的药理学激活能够调节感觉神经元活动并引发伤害性效应。在本研究中,我们阐述了一种控制机制,该机制使Runx1 runt结构域转录因子能够产生这些感觉GPCRs的分区表达。MrgA、MrgB和MrgC亚类的表达局限于一个“A/B/C”神经元分区,该分区短暂表达Runx1(或不表达Runx1),而MrgD的表达则局限于持续表达Runx1的“D”分区。所有Mrg基因的表达最初都需要Runx1。然而,在发育后期,Runx1成为MrgA/B/C基因的抑制因子。因此,MrgA/B/C的表达仅在Runx1-“A/B/C”分区持续存在。在delta446小鼠中,Runx1缺乏C末端抑制结构域,MrgA/B/C基因的表达显著扩展到Runx1+“D”分区。然而,MrgD的表达在“D”分区对Runx1介导的抑制具有抗性。因此,Runx1+和Runx1-分区的形成,以及Mrg基因对Runx1介导的抑制的不同反应,导致了MrgA/B/C与MrgD基因的分区表达。在MrgA/B/C分区内,表达MrgB4的神经元仅支配多毛皮肤。在这里我们发现,骨形态发生蛋白介导信号传导的下游成分Smad4是MrgB4表达所选择性需要的。我们的研究提出了新的证据,表明感觉亚型的特化在围产期和产后发育过程中逐步建立。