Department of Cell and Developmental Biology, University College London, WC1E 6BT, United Kingdom, Department of Pharmacology and Toxicology, University Hospital Jena, Friedrich-Schiller University, 07747 Jena, Germany, and Department of Immunology, Monash University, Alfred Medical Research and Education Precinct (AMREP), Melbourne, Victoria 3000, Australia.
J Neurosci. 2013 Oct 30;33(44):17527-37. doi: 10.1523/JNEUROSCI.0857-13.2013.
Gonadotropin-releasing hormone (GnRH) neurons are neuroendocrine cells, located in the hypothalamus, that play an essential role in mammalian reproduction. These neurons originate in the nasal placode and migrate during embryonic development, in association with olfactory/vomeronasal nerves, first in the nose, then through the cribriform plate to enter the forebrain, before settling in the hypothalamus. One of the molecules required for their early migration in the nose is the chemokine CXCL12, which is expressed in the embryonic nasal mesenchyme in an increasing ventral to dorsal gradient, presumably guiding GnRH neurons toward the forebrain. Mice lacking CXCR4, the receptor for CXCL12, exhibit defective GnRH cell movement and a significant reduction in their number, suggesting that CXCL12/CXCR4 signaling is important in the migration and survival of these neurons. Here, we investigated the role of the more recently identified second CXCL12 receptor, CXCR7, in GnRH neuron development. We demonstrate that CXCR7 is expressed along the migratory path of GnRH neurons in the nasal cavity and, although not expressed by GnRH neurons, it affects their migration as indicated by the ectopic accumulation of these cells in the nasal compartment in CXCR7(-/-) mice. Absence of CXCR7 caused abnormal accumulation of CXCL12-RFP at CXCR4-positive sites in the nasal area of CXCL12-RFP-transgenic mice and excessive CXCL12-dependent intracellular clustering of CXCR4 in GnRH neurons, suggesting internalization. These findings imply that CXCR7 regulates CXCL12 availability by acting as a scavenger along the migratory path of GnRH neurons and, thus, influences the migration of these cells in a noncell-autonomous manner.
促性腺激素释放激素（GnRH）神经元是位于下丘脑的神经内分泌细胞，在哺乳动物生殖中发挥着重要作用。这些神经元起源于鼻基板，并在胚胎发育过程中迁移，与嗅觉/犁鼻神经一起，首先在鼻子中迁移，然后穿过筛板进入前脑，最后定居在下丘脑。在鼻子中早期迁移所需的一种分子是趋化因子 CXCL12，它在胚胎鼻腔基质中呈从腹侧向背侧逐渐增加的梯度表达，可能引导 GnRH 神经元向大脑前方向迁移。缺乏趋化因子 CXCL12 的受体 CXCR4 的小鼠表现出 GnRH 细胞运动缺陷和数量显著减少，表明 CXCL12/CXCR4 信号在这些神经元的迁移和存活中很重要。在这里，我们研究了最近发现的第二个 CXCL12 受体 CXCR7 在 GnRH 神经元发育中的作用。我们证明 CXCR7 在 GnRH 神经元在鼻腔中的迁移路径上表达，尽管它不被 GnRH 神经元表达，但它会影响它们的迁移，因为在 CXCR7(-/-) 小鼠中这些细胞异常积累在鼻腔隔室中。CXCR7 的缺失导致 CXCL12-RFP 在 CXCL12-RFP 转基因小鼠的鼻腔区域中 CXCR4 阳性部位的异常积累，以及 GnRH 神经元中 CXCR4 过度依赖 CXCL12 的细胞内聚集，提示内化。这些发现表明，CXCR7 通过作为 GnRH 神经元迁移路径上的清道夫发挥作用来调节 CXCL12 的可用性，并以非细胞自主的方式影响这些细胞的迁移。
