Haploinsufficiency of retinoic acid-induced 1 (RAI1) is responsible for Smith–Magenis syndrome (SMS), a childhood neurodevelopmental disorder associated with hyperphagia, obesity and autistic features. We previously showed that constitutive inactivation of one or both copies of Rai1 in the germline or developing brain induces SMS-like neurobehavioral deficits and obesity in mice. By contrast, the postnatal function of Rai1 is unclear. Here, we globally deleted one or both copies of Rai1 during two postnatal developmental windows by generating an inducible Rai1 knockout mouse model. We found that delayed Rai1 deletion at 3 or 8 weeks of age had no effect on neurobehavioral functions but resulted in adult-onset obesity and decreased expression of brain-derived neurotrophic factor (Bdnf) in the hypothalamus. Remarkably, genetic overexpression of human Bdnf in Rai1 heterozygous mice reversed SMS-like obesity, hyperphagia, metabolic syndrome-like features and hyposociability. Increasing Bdnf signaling in the paraventricular nucleus of the hypothalamus or the ventromedial nucleus of the hypothalamus was sufficient to mediate the anti-obesity effect. Our work identifies the function of Rai1 in different temporal windows after birth and provides in vivo evidence that increasing Bdnf signaling is therapeutically effective in a preclinical mouse model of SMS.

中文翻译：

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Rai1 功能的时间解剖揭示了脑源性神经营养因子作为 Smith-Magenis 综合征的潜在治疗靶点

维甲酸诱导的单倍体不足 1 (RAI1) 是导致 Smith-Magenis 综合征 (SMS) 的原因，这是一种与食欲过盛、肥胖和自闭症特征相关的儿童神经发育障碍。我们之前表明，在生殖系或发育中的大脑中，一个或两个 Rai1 拷贝的组成性失活会在小鼠中诱导类似 SMS 的神经行为缺陷和肥胖。相比之下，Rai1 的产后功能尚不清楚。在这里，我们通过生成可诱导的 Rai1 敲除小鼠模型在两个出生后发育窗口期间全局删除了 Rai1 的一个或两个副本。我们发现在 3 周或 8 周龄时延迟 Rai1 缺失对神经行为功能没有影响，但会导致成年期肥胖和下丘脑中脑源性神经营养因子 (Bdnf) 的表达降低。值得注意的是，Rai1 杂合子小鼠中人类 Bdnf 的基因过表达逆转了 SMS 样肥胖、食欲过盛、代谢综合征样特征和社交能力不足。在下丘脑室旁核或下丘脑腹内侧核中增加 Bdnf 信号足以介导抗肥胖作用。我们的工作确定了 Rai1 在出生后不同时间窗口中的功能，并提供了体内证据，证明增加 Bdnf 信号在 SMS 的临床前小鼠模型中具有治疗效果。