文献类型：期刊文献

英文题名：Notch-Rbpj signaling is required for the development of noradrenergic neurons in the mouse locus coeruleus

作者：Shi, Ming[1,2,3];Hu, Ze-Lan[1,2,4];Zheng, Min-Hua[5];Song, Ning-Ning[1,2];Huang, Ying[1,2];Zhao, Gang[3];Han, Hua[5];Ding, Yu-Qiang[1,2]

机构：[1]Tongji Univ, Sch Med, Minist Educ China, Key Lab Arrhythmias,East Hosp, Shanghai 200092, Peoples R China;[2]Tongji Univ, Sch Med, Dept Anat & Neurobiol, Shanghai 200092, Peoples R China;[3]Fourth Mil Med Univ, Xijing Hosp, Dept Neurol, Xian 710032, Peoples R China;[4]E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China;[5]Fourth Mil Med Univ, Dept Med Genet & Dev Biol, Xian 710032, Peoples R China

年份：2012

卷号：125

期号：18

起止页码：4320

外文期刊名：JOURNAL OF CELL SCIENCE

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000310796800016)】；

基金：This work was supported by the National Natural Science Foundation of China [grant numbers 31030034, 31170801, 81101026, 31100788]; and Ministry of Science and Technology of China [grant numbers 2011CB510005 and 2012CB966904].

语种：英文

外文关键词：Rbpj; Notch signaling; Locus coeruleus; Rhombomere 1; Hes1; Ascl1

摘要：The locus coeruleus (LC) is the main source of noradrenaline in the brain and is implicated in a broad spectrum of physiological and behavioral processes. However, genetic pathways controlling the development of noradrenergic neurons in the mammalian brain are largely unknown. We report here that Rbpj, a key nuclear effector in the Notch signaling pathway, plays an essential role in LC neuron development in the mouse. Conditional inactivation of Rbpj in the dorsal rhombomere (r) 1, where LC neurons are born, resulted in a dramatic increase in the number of Phox2a- and Phox2b-expressing early-differentiating LC neurons, and dopamine-beta-hydroxylase- and tyrosine-hydroxylase-expressing late-differentiating LC neurons. In contrast, other neuronal populations derived from the dorsal r1 were either reduced or unchanged. In addition, a drastic upregulation of Ascl1, an essential factor for noradrenergic neurogenesis, was observed in dorsal r1 of conditional knockout mice. Through genomic sequence analysis and EMSA and ChIP assays, a conserved Rbpj-binding motif was identified within the Ascl1 promoter. A luciferase reporter assay revealed that Rbpj per se could induce Ascl1 transactivation but this effect was counteracted by its downstream-targeted gene Hes1. Moreover, our in vitro gene transfection and in ovo electroporation assays showed that Rbpj upregulated Ascl1 expression when Hes1 expression was knocked down, although it also exerted a repressive effect on Ascl1 expression in the presence of Hes1. Thus, our results provide the first evidence that Rbpj functions as a key modulator of LC neuron development by regulating Ascl1 expression directly, and indirectly through its target gene Hes1.