Coordinated regulation of gene expression by Brn3a in developing sensory ganglia. Mus musculus

Mice lacking the POU-domain transcription factor Brn3a exhibit marked defects in sensory axon growth and abnormal sensory apoptosis. We have determined the regulatory targets of Brn3a in the developing trigeminal ganglion using microarray analysis of Brn3a mutant mice. These results show that Brn3 mediates the coordinated expression of neurotransmitter systems, ion channels, structural components of axons and inter- and intracellular signaling systems. Loss of Brn3a also results in the ectopic expression of transcription factors normally detected in earlier developmental stages and in other areas of the nervous system. Target gene expression is normal in heterozygous mice, consistent with prior work showing that autoregulation by Brn3a results in gene dosage compensation. Detailed examination of the expression of several of these downstream genes reveals that the regulatory role of Brn3a in the trigeminal ganglion appears to be conserved in more posterior sensory ganglia but not in the CNS neurons that express this factor. Keywords: Gene expression in the developing nervous system Overall design: Microarrays used to compare the patterns of gene expression in the trigeminal ganglia of Brn3a knockout and wild-type mice. Embryonic day 13.5 (E13.5) was chosen because at this point in development mutant mice exhibit major defects in sensory axon growth, but have yet to undergo the period of extensive sensory neuron death associated with later stages.

缺失POU结构域转录因子（POU-domain transcription factor）Brn3a的小鼠，可出现显著的感觉轴突生长缺陷与异常感觉神经元凋亡。本研究通过对Brn3a突变小鼠开展微阵列（microarray）分析，鉴定了发育阶段三叉神经节内Brn3a的调控靶基因。研究结果表明，Brn3a可介导神经递质系统、离子通道、轴突结构组分以及细胞间与细胞内信号转导系统的协同表达。Brn3a缺失还可引发通常仅在发育早期阶段及神经系统其他区域中检测到的转录因子发生异位表达。杂合子小鼠的靶基因表达水平正常，这与此前研究揭示的Brn3a自调控可产生基因剂量补偿效应的结论一致。对其中数条下游基因的表达进行详细分析后发现，Brn3a在三叉神经节中的调控作用在更靠后的感觉神经节中具有保守性，但在表达该因子的中枢神经系统（central nervous system，CNS）神经元中则无此保守性。
关键词：发育中神经系统的基因表达
实验设计方案：通过微阵列（microarray）对比Brn3a敲除型与野生型小鼠三叉神经节的基因表达模式。本研究选取胚胎第13.5天（E13.5）作为检测节点，原因在于该发育阶段的突变小鼠已出现感觉轴突生长的显著缺陷，但尚未进入与后续发育阶段相关的大规模感觉神经元死亡时期。