Hirsch M R, Tiveron M C, Guillemot F, Brunet J F, Goridis C
Laboratoire de Génétique et Physiologie du Développement, Institute de Biologie du Développement de Marseille, CNRS/INSERM/Université de la Méditerranée, Campus de Luminy, Marseille, France.
Development. 1998 Feb;125(4):599-608. doi: 10.1242/dev.125.4.599.
Mash1, a mammalian homologue of the Drosophila proneural genes of the achaete-scute complex, is transiently expressed throughout the developing peripheral autonomic nervous system and in subsets of cells in the neural tube. In the mouse, targeted mutation of Mash1 has revealed a role in the development of parts of the autonomic nervous system and of olfactory neurons, but no discernible phenotype in the brain has been reported. Here, we show that the adrenergic and noradrenergic centres of the brain are missing in Mash1 mutant embryos, whereas most other brainstem nuclei are preserved. Indeed, the present data together with the previous results show that, except in cranial sensory ganglia, Mash1 function is essential for the development of all central and peripheral neurons that express noradrenergic traits transiently or permanently. In particular, we show that, in the absence of MASH1, these neurons fail to initiate expression of the noradrenaline biosynthetic enzyme dopamine beta-hydroxylase. We had previously shown that all these neurons normally express the homeodomain transcription factor Phox2a, a positive regulator of the dopamine beta-hydroxylase gene and that a subset of them depend on it for their survival. We now report that expression of Phox2a is abolished or massively altered in the Mash1-/- mutants, both in the noradrenergic centres of the brain and in peripheral autonomic ganglia. These results suggest that MASH1 controls noradrenergic differentiation at least in part by controlling expression of Phox2a and point to fundamental homologies in the genetic circuits that determine the noradrenergic phenotype in the central and peripheral nervous system.
Mash1是果蝇achaete - scute复合体中神经原性基因的哺乳动物同源物，在整个发育中的外周自主神经系统以及神经管中的细胞亚群中短暂表达。在小鼠中，Mash1的靶向突变揭示了其在自主神经系统部分以及嗅觉神经元发育中的作用，但尚未有关于其在大脑中可识别表型的报道。在此，我们发现Mash1突变胚胎中大脑的肾上腺素能和去甲肾上腺素能中枢缺失，而大多数其他脑干核得以保留。事实上，目前的数据与先前的结果共同表明，除了颅感觉神经节外，Mash1的功能对于所有短暂或永久表达去甲肾上腺素能特征的中枢和外周神经元的发育至关重要。特别是，我们发现，在缺乏MASH1的情况下，这些神经元无法启动去甲肾上腺素生物合成酶多巴胺β - 羟化酶的表达。我们之前已经表明，所有这些神经元通常表达同源结构域转录因子Phox2a，它是多巴胺β - 羟化酶基因的正向调节因子，并且其中一部分神经元的存活依赖于它。我们现在报道，在Mash1 - / - 突变体中，Phox2a的表达在大脑的去甲肾上腺素能中枢和外周自主神经节中均被消除或大量改变。这些结果表明，MASH1至少部分地通过控制Phox2a的表达来控制去甲肾上腺素能分化，并指出在决定中枢和外周神经系统中去甲肾上腺素能表型的遗传回路中存在基本的同源性。
