酪氨酸羟化酶条件性 Olfr78 基因敲除小鼠的颈动脉体功能

Function Pub Date : 2024-02-22 DOI:10.1093/function/zqae010
Olalla Colinas, Peter Mombaerts, J. López-Barneo, Patricia Ortega-Sáenz
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引用次数: 0

摘要

Olfr78 基因编码一种 G 蛋白偶联受体,该受体在嗅觉神经元中表达,在嗅觉神经元中起传统气味受体的作用,同时也在几个异位位点中表达,其功能尚不十分清楚。Olfr78 是颈动脉体(CB)神经胶质细胞中表达量最高的 mRNA 物种之一。这些细胞是典型的对氧气(O2)敏感的动脉化学感受器,当氧气张力降低(缺氧)时,它们会激活呼吸中枢,诱导过度换气。有人提出,Olfr78 是一种乳酸受体,血液中乳酸的增加会激活神经胶质细胞,从而介导缺氧通气反应(HVR)。然而,一些研究小组对这一提议提出了质疑,他们的研究表明,Olfr78 并非生理上相关的乳酸受体,Olfr78 基因敲除小鼠基于氧气的呼吸调节并不受影响。另一项研究报告称,Olfr78基因敲除小鼠对轻度缺氧的全身反应和CB反应发生了改变。这些机体表型可能是由于组成型 Olfr78 基因敲除突变在各种 CB 细胞类型和/或该基因表达的各种器官中产生的多效应。因此,为了进一步确定Olfr78在CB胶束细胞中的功能作用,我们在这里产生了一个条件性Olfr78基因敲除小鼠品系,然后通过与酪氨酸羟化酶特异性Cre驱动品系杂交(TH-Olfr78 KO小鼠),将基因敲除限制在胶束细胞和其他儿茶酚胺能细胞中。我们发现,TH-Olfr78 KO 小鼠的 HVR 正常。有趣的是,TH-Olfr78 KO 小鼠的神经胶质细胞表现出分子和电生理学改变,分泌囊泡中的多巴胺含量和神经分泌活性也有所降低。这些功能特征与野生型小鼠的 CB 神经母细胞相似。我们认为,尽管Olfr78对CB O2感应并不是必需的,但成熟的神经胶质细胞的表型规格化需要Olfr78依赖途径的激活。
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Carotid Body Function in Tyrosine Hydroxylase Conditional Olfr78 Knockout Mice
The Olfr78 gene encodes a G-protein coupled receptor that is expressed in olfactory sensory neurons, where it functions as a conventional odorant receptor, and also in several ectopic sites, where its function is not well understood. Olfr78 is one of the most highly expressed mRNA species in glomus cells of the carotid body (CB). These cells are the prototypical oxygen (O2) sensitive arterial chemoreceptors, which, in response to lowered O2 tension (hypoxia), activate the respiratory centers to induce hyperventilation. It has been proposed that Olfr78 is a lactate receptor and that glomus cell activation by the increase in blood lactate mediates the hypoxic ventilatory response (HVR). However, this proposal has been challenged by several groups showing that Olfr78 is not a physiologically relevant lactate receptor and that the O2-based regulation of breathing is not affected in Olfr78 knockout mice. In another study, Olfr78 knockout mice were reported to have altered systemic and CB responses to mild hypoxia. These organismal phenotypes could result from pleiotropic effects of the constitutive Olfr78 knockout mutations in the various CB cell types and/or various organs where this gene is expressed. Therefore, to further characterize the functional role of Olfr78 in CB glomus cells, we here generated a conditional Olfr78 knockout mouse strain and then restricted the knockout to glomus cells and other catecholaminergic cells by crossing with a tyrosine hydroxylase-specific Cre driver strain (TH-Olfr78 KO mice). We find that TH-Olfr78 KO mice have a normal HVR. Interestingly, glomus cells of TH-Olfr78 KO mice exhibit molecular and electrophysiological alterations as well as a reduced dopamine content in secretory vesicles and neurosecretory activity. These functional characteristics resemble those of CB neuroblasts in wild-type mice. We suggest that, although Olfr78 is not essential for CB O2 sensing, activation of Olfr78-dependent pathways is required for the phenotypic specification of mature glomus cells.
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