Murine Arcuate Nucleus Kisspeptin Neurons Communicate with GnRH Neurons In Utero
Murine Arcuate Nucleus Kisspeptin Neurons Communicate with GnRH Neurons In Utero
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DOI：
10.1523/jneurosci.5123-13.2014
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发表时间：
2014-03-05
影响因子：
5.3
通讯作者：
Boehm, Ulrich
中科院分区：
文献类型：
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作者：
Kumar, Devesh;Freese, Maria;Boehm, Ulrich
青春期是生殖发育从幼年期到成年期的过渡期，取决于促性腺激素释放激素（GnRH）神经元的活性。GnRH神经元最初在子宫内被激活，但在整个幼年期保持静止。GnRH神经元的过早再激活导致小鼠和人类的性早熟，但GnRH神经元活性的发育控制机制仍不清楚。神经肽kisspeptin是GnRH神经元的一种有效激活剂，被认为是触发青春期的关键许可信号，也是成年女性下丘脑-垂体-性腺轴的主要调节因子，但在青春期开始前，发育中的大脑中的神经元却产生了这种神经肽。因此，控制生殖成熟时间的神经回路仍然难以捉摸。在这里，我们描绘了潜在的神经回路，使用条件遗传跨突触追踪雌性小鼠胚胎。我们发现弓状核（ARC）中的kisspeptin产生神经元已经与子宫内特定的GnRH神经元亚群进行了交流。我们发现ARC kisspeptin神经元是GnRH神经元的上游，并且GnRH神经元与ARC kisspeptin神经元的连接不依赖于它们在大脑中的空间位置。此外，我们证明，ARC kisspeptin和GnRH神经元之间的神经回路是完全建立和操作出生前。最后，我们发现，大多数GnRH神经元表达的kisspeptin受体GPR 54电路形成后，这表明信号系统涉及守门青春期成为在胚胎中运作。
Puberty is a transition period of reproductive development from juvenile stages to adulthood and depends upon the activity of gonadotropin-releasing hormone (GnRH) neurons. GnRH neurons are initially activated in utero but remain quiescent throughout the juvenile period. Premature reactivation of GnRH neurons results in precocious puberty in mice and humans, but the mechanisms underlying developmental control of GnRH neuron activity remain unknown. The neuropeptide kisspeptin, a potent activator of GnRH neurons that is implicated as a critical permissive signal triggering puberty and a major regulator of the adult female hypothalamus-pituitary-gonadal axis, is paradoxically produced by neurons in the developing brain well before puberty onset. Thus, the neural circuits controlling the timing of reproductive maturation remain elusive. Here, we delineate the underlying neural circuitry using conditional genetic transsynaptic tracing in female mouse embryos. We find that kisspeptin-producing neurons in the arcuate nucleus (ARC) already communicate with a specific subset of GnRH neurons in utero. We show that ARC kisspeptin neurons are upstream of GnRH neurons, and that GnRH neuron connectivity to ARC kisspeptin neurons does not depend on their spatial position in the brain. Furthermore, we demonstrate that the neural circuits between ARC kisspeptin and GnRH neurons are fully established and operative before birth. Finally, we find that most GnRH neurons express the kisspeptin receptor GPR54 upon circuit formation, suggesting that the signaling system implicated in gatekeeping puberty becomes operative in the embryo.