Disrupted-in-Schizophrenia-1 is essential for normal hypothalamic-pituitary-interrenal (HPI) axis function.
Disrupted-in-Schizophrenia-1 is essential for normal hypothalamic-pituitary-interrenal (HPI) axis function.
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DOI：
10.1093/hmg/ddx076
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发表时间：
2017-06-01
影响因子：
3.5
通讯作者：
Watt PJ
中科院分区：
文献类型：
--
作者：
Eachus H;Bright C;Cunliffe VT;Placzek M;Wood JD;Watt PJ
精神疾病的出现是由于遗传和环境因素的相互作用，包括压力。对啮齿动物的研究表明，精神分裂症1（DISC 1）的突变体是一种公认的精神疾病遗传风险因素，在应对压力时表现出异常行为，但DISC 1影响压力反应的机制仍然知之甚少。使用两条斑马鱼disc 1纯合突变线，我们调查的行为和功能的下丘脑-垂体-肾间（HPI）轴，鱼相当于下丘脑-垂体-肾上腺（HPA）轴。在这里，我们表明，DISC 1在应激反应中的作用是进化保守的，DISC 1是必不可少的HPI轴的正常功能。成年斑马鱼disc 1纯合突变体对应激表现出异常的行为反应。我们的研究表明，在胚胎中，disc 1在下丘脑的神经祖细胞中表达，下丘脑是脊椎动物大脑的一个保守区域，集中控制对环境压力的反应。在disc 1突变的胚胎中，增殖的rx 3+下丘脑祖细胞不能正常维持，神经元分化受到损害：rx 3衍生的ff 1b+神经元，涉及焦虑相关行为，促肾上腺皮质激素释放激素（crh）神经元，应激轴的关键调节器，发育异常，rx 3衍生的pomc+神经元紊乱。下丘脑发育异常与功能失调的行为和神经内分泌应激反应有关。与野生型的同胞相比，disc 1突变的幼虫表现出crh水平的改变，在压力下不能上调皮质醇水平，也不能调节鱼群的凝聚力，这表明了异常的社会行为。这些数据表明，disc 1是下丘脑的正常发育和HPA/HPI轴的正确功能所必需的。
Psychiatric disorders arise due to an interplay of genetic and environmental factors, including stress. Studies in rodents have shown that mutants for Disrupted-In-Schizophrenia-1 (DISC1), a well-accepted genetic risk factor for mental illness, display abnormal behaviours in response to stress, but the mechanisms through which DISC1 affects stress responses remain poorly understood. Using two lines of zebrafish homozygous mutant for disc1, we investigated behaviour and functioning of the hypothalamic-pituitary-interrenal (HPI) axis, the fish equivalent of the hypothalamic-pituitary-adrenal (HPA) axis. Here, we show that the role of DISC1 in stress responses is evolutionarily conserved and that DISC1 is essential for normal functioning of the HPI axis. Adult zebrafish homozygous mutant for disc1 show aberrant behavioural responses to stress. Our studies reveal that in the embryo, disc1 is expressed in neural progenitor cells of the hypothalamus, a conserved region of the vertebrate brain that centrally controls responses to environmental stressors. In disc1 mutant embryos, proliferating rx3+ hypothalamic progenitors are not maintained normally and neuronal differentiation is compromised: rx3-derived ff1b+ neurons, implicated in anxiety-related behaviours, and corticotrophin releasing hormone (crh) neurons, key regulators of the stress axis, develop abnormally, and rx3-derived pomc+ neurons are disorganised. Abnormal hypothalamic development is associated with dysfunctional behavioural and neuroendocrine stress responses. In contrast to wild type siblings, disc1 mutant larvae show altered crh levels, fail to upregulate cortisol levels when under stress and do not modulate shoal cohesion, indicative of abnormal social behaviour. These data indicate that disc1 is essential for normal development of the hypothalamus and for the correct functioning of the HPA/HPI axis.