Pontine norepinephrine defects in Mecp2-null mice involve deficient expression of dopamine beta-hydroxylase but not a loss of catecholaminergic neurons.
Pontine norepinephrine defects in Mecp2-null mice involve deficient expression of dopamine beta-hydroxylase but not a loss of catecholaminergic neurons.
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DOI：
10.1016/j.bbrc.2010.02.156
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发表时间：
2010-04-02
影响因子：
3.1
通讯作者：
Jiang, Chun
中科院分区：
文献类型：
--
作者：
Zhang, Xiaoli;Su, Junda;Rojas, Asheebo;Jiang, Chun
关键词：
Rett综合征是一种由MeCP2基因突变引起的神经发育障碍。在RTT患者和MeCP2缺失(MeCP2−/Y)小鼠中，去甲肾上腺素(NE)含量显著下降，这可能在RTT的呼吸性心律失常、睡眠障碍和猝死中起作用。然而，NE缺陷的潜在机制尚不完全清楚。NE缺陷可能是由于NE生物合成减少、儿茶酚胺能神经元丢失或两者兼而有之。虽然酪氨酸羟化酶(TH)缺乏已被证实，但多巴胺β羟基酶(DBH)，多巴胺转化为NE的关键酶，也可能受到影响。为了测试这些可能性，我们研究了呼吸异常的MeCP2−/Y小鼠脑桥儿茶酚胺能神经元中DBH基因和蛋白水平的表达。与WT小鼠相比，2个月龄的MeCP2−/Y小鼠蓝斑(LC)区胸径和TH的蛋白和基因表达水平均降低约50%。MeCP2−/Y小鼠LC神经元内胸腺激素和TH免疫反应均显著降低。在MeCP2−/Y小鼠中，没有证据表明含有TH或DBH的神经元存在选择性缺陷，因为几乎所有TH阳性细胞都表达DBH。通过对LC中TH免疫反应阳性细胞的计数，我们发现与野生型相比，MeCP2−/Y小鼠仅丢失了~5%的儿茶酚胺能神经元，尽管其LC体积缩小了~15%。这些结果有力地表明，MeCP2−/Y小鼠的NE缺陷可能是由于LC中TH和DBH的表达不足，而没有明显的儿茶酚胺能神经元的丢失。
Rett syndrome is a neurodevelopmental disorder caused by Mecp2 gene mutations. In RTT patients and Mecp2-null (Mecp2−/Y) mice, norepinephrine (NE) content drops significantly, which may play a role in breathing arrhythmia, sleep disorders and sudden death in RTT. However, the underlying mechanisms for the NE defect are not fully understood. The NE defect may result from decreased NE biosynthesis, loss of catecholaminergic neurons or both. Although deficiency in tyrosine hydroxylase (TH) has been demonstrated, it is possible that dopamine β-hydroxylase (DBH), the critical enzyme converting dopamine to NE, is also affected. To test these possibilities, we studied DBH expressions at mRNA and protein levels in pontine catecholaminergic neurons of Mecp2−/Y mice identified with breathing abnormalities. In comparison to the WT, Mecp2−/Y mice at 2 months of age showed ~50% decrease in the expressions of DBH and TH, at both protein and mRNA levels in the locus coeruleus (LC) region. Consistently, DBH and TH immunoreactivity was markedly decreased in LC neurons of Mecp2−/Y mice. No evidence was found for selective deficiency in TH- or DBH-containing neurons in Mecp2−/Y mice, as almost all TH-positive cells expressed DBH. By counting TH-immunoreactive cells in the LC, we found that the Mecp2−/Y mice lost only ~5% of the catecholaminergic neurons as compared to wild-type, although their LC volume shrank by ~15%. These results strongly suggest that the NE defect in Mecp2−/Y mice is likely to result from deficient expression of not only TH but also DBH without significant loss of catecholaminergic neurons in the LC.
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影响因子：
158.5
作者：
ZOGHBI, HY;PERCY, AK;RICCARDI, VM
通讯作者：
RICCARDI, VM
影响因子：
2.5
作者：
Ide, S;Itoh, M;Goto, Y
通讯作者：
Goto, Y
DOI：
10.1073/pnas.0912257106
发表时间：
2009-12-22
影响因子：
11.1
作者：
Samaco, Rodney C.;Mandel-Brehm, Caleigh;Neul, Jeffrey L.
通讯作者：
Neul, Jeffrey L.
DOI：
10.1073/pnas.0707442104
发表时间：
2007-12-04
影响因子：
11.1
作者：
Yasui, Dag H.;Peddada, Sailaja;LaSalle, Janine M.
通讯作者：
LaSalle, Janine M.
影响因子：
5.3
作者：
Viemari, JC;Roux, JC;Hilaire, G
通讯作者：
Hilaire, G