Insm1 (IA-1) is a crucial component of the transcriptional network that controls differentiation of the sympathoadrenal lineage
Insm1 (IA-1) is a crucial component of the transcriptional network that controls differentiation of the sympathoadrenal lineage
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DOI：
10.1242/dev.011783
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发表时间：
2008-02-01
期刊：
影响因子：
4.6
通讯作者：
Birchmeier, Carmen
中科院分区：
文献类型：
--
作者：
Wildner, Hendrik;Gierl, Mathias S.;Birchmeier, Carmen
Insm1 （IA-1）编码锌指因子，该因子在发育中的神经系统中表达。我们在这里证明，在Insm1突变小鼠中，交感神经-肾上腺谱系的发育严重受损。通过神经元亚型特异性基因（如Th和Dbh）的表达来评估，交感神经-肾上腺前体的分化以明显的方式延迟，并伴有增殖减少。交感神经元最终克服分化阻滞并正常成熟，但交感神经节仍然很小。相反，肾上腺染色质细胞不发生终末分化。转录因子Mash1 （Ascl1）、Phox2a、Gata3和Hand2（以前的dHand）控制着交感肾上腺前体细胞的分化，它们在Insm1突变小鼠中的失调表达表明Insm1在控制该谱系分化的转录网络中起作用。Mash1和Insm1表型之间的显著相似性是显而易见的，这表明Insm1可能介导了Mash1在交感神经肾上腺前体亚型特异性分化中的功能。去甲肾上腺素是由交感肾上腺细胞产生的主要儿茶酚胺，是胎儿存活所必需的。我们证明Insm1突变小鼠的胎儿死亡是由儿茶酚胺缺乏引起的，这突出了Insm1在交感神经-肾上腺谱系发育中的重要性。
Insm1 (IA-1) encodes a Zn-finger factor that is expressed in the developing nervous system. We demonstrate here that the development of the sympatho-adrenal lineage is severely impaired in Insm1 mutant mice. Differentiation of sympatho-adrenal precursors, as assessed by the expression of neuronal subtype-specific genes such as Th and Dbh, is delayed in a pronounced manner, which is accompanied by a reduced proliferation. Sympathetic neurons eventually overcome the differentiation blockade and mature correctly, but sympathetic ganglia remain small. By contrast, terminal differentiation of adrenal chromaffin cells does not occur. The transcription factors Mash1 (Ascl1), Phox2a, Gata3 and Hand2 (previously dHand) control the differentiation of sympatho- adrenal precursor cells, and their deregulated expression in Insm1 mutant mice demonstrates that Insm1 acts in the transcriptional network that controls differentiation of this lineage. Pronounced similarities between Mash1 and Insm1 phenotypes are apparent, which suggests that Insm1 might mediate aspects of Mash1 function in the subtype- specific differentiation of sympatho-adrenal precursors. Noradrenaline is the major catecholamine produced by developing sympatho-adrenal cells and is required for fetal survival. We demonstrate that the fetal lethality of Insm1 mutant mice is caused by catecholamine deficiency, which highlights the importance of Insm1 in the development of the sympatho-adrenal lineage.