Genetic dissection of puberty in mice
Genetic dissection of puberty in mice
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DOI：
10.1113/expphysiol.2013.071928
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发表时间：
2013-11-01
影响因子：
2.7
通讯作者：
Boehm, Ulrich
中科院分区：
文献类型：
--
作者：
Kumar, Devesh;Boehm, Ulrich
确定控制促性腺激素释放激素（GnRH）释放的神经机制对于理解脊椎动物生殖生理的中枢控制具有关键意义。对kisspeptin和GPR54神经元进行定向基因操作，为研究生殖成熟过程中GnRH释放的调控机制提供了新的思路。虽然有条件地切除kisspeptin神经元中的雌激素受体（一种基因）会导致雌性小鼠的青春期显著提前，但这些动物随后的青春期成熟却被阻止，因为它们无法获得正常的排卵周期。这些数据表明，在雌性小鼠的青春期发育过程中，kisspeptin神经元中有两种依赖雌激素受体a的机制，一种是“刹车”机制，另一种是“加速器”机制，它们依次被操作，以控制并激活GnRH的释放。在另一种不同的实验方法中，我们从小鼠大脑中移除整个kisspeptin神经元，从而从控制生殖的神经回路中移除。令人惊讶的是，kisspeptin神经元消融对女性青春期的开始没有影响。此外，这些动物获得了规律的排卵周期和可生育能力。与此一致的是，缺乏表达kisspeptin受体GPR54的神经元的雌性小鼠也具有生育能力，这表明在缺乏kisspeptin/GPR54信号传导的情况下，雌性生殖成熟。然而，成年小鼠的kisspeptin神经元急性消融会抑制生育能力，这表明在生殖神经回路形成过程中，kisspeptin神经元的缺失存在发育补偿。最后，我们发现kisspeptin神经元在出生后第20天就成为小鼠大脑生殖神经回路中不可或缺的一部分。
Determining the neural mechanisms controlling gonadotrophin-releasing hormone (GnRH) release is of pivotal importance in understanding central control of reproductive physiology in vertebrates. Targeted genetic manipulation of kisspeptin and GPR54 neurons has provided new insights into the mechanisms modulating GnRH release and thereby regulating hypothalamic-pituitary-gonadal axis activity during reproductive maturation. While conditional ablation of the oestrogen receptor a gene in kisspeptin neurons results in a dramatic advancement of the onset of puberty in female mice, subsequent pubertal maturation is arrested in these animals, as they fail to acquire normal ovulatory cyclicity. These data suggest that two oestrogen receptor a-dependent mechanisms, one a 'brake' and the other an 'accelerator', are sequentially operated in kisspeptin neurons during pubertal development of female mice to gate and then to activate GnRH release. In a different experimental approach, we removed entire kisspeptin neurons from the mouse brain and thus from the neural circuits controlling reproduction. Surprisingly, the onset of puberty in females was unaffected by kisspeptin neuron ablation. Furthermore, the animals attained regular ovulatory cyclicity and were fertile. Consistent with this, female mice lacking neurons that express the kisspeptin receptor GPR54 were also fertile, suggesting female reproductive maturation in the absence of kisspeptin/GPR54 signalling. However, acute kisspeptin neuron ablation in adult mice inhibited fertility, indicating that there is developmental compensation for the loss of kisspeptin neurons during reproductive neural circuit formation. Finally, we showed that kisspeptin neurons become an indispensable part of reproductive neural circuitry in the mouse brain before postnatal day 20.