Defective migration of neuroendocrine GnRH cells in human arrhinencephalic conditions
Defective migration of neuroendocrine GnRH cells in human arrhinencephalic conditions
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DOI：
10.1172/jci43699
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发表时间：
2010-10-01
影响因子：
15.9
通讯作者：
Hardelin, Jean-Pierre
中科院分区：
文献类型：
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作者：
Teixeira, Luis;Guimiot, Fabien;Hardelin, Jean-Pierre
Kallmann综合征（KS）患者患有由促性腺激素释放激素（GnRH）缺乏和与嗅球发育不全相关的嗅觉缺陷引起的低促性腺激素性性腺功能减退症。根据X染色体连锁型疾病影响胎儿的研究结果，已表明KS性腺功能减退是由于神经内分泌GnRH 1细胞从鼻上皮向前脑的胚胎迁移失败所致。我们想知道这种独特的观察结果是否可以扩展到其他发育障碍，包括无脑畸形。因此，我们研究了不同的arrhinencephalic疾病，特别是X-连锁KS，CHARGE综合征，三体13，三体18，使用免疫组织化学的影响胎儿的GnRH 1细胞的位置。所有无鼻脑胎儿的视前区和下丘脑区中检测到很少或没有神经内分泌GnRH 1细胞，而对照胎儿中存在大量这些细胞。在所有无鼻脑畸形胎儿中，许多GnRH 1细胞出现在额鼻区，这是它们迁移路径的第一部分，因为嗅觉神经纤维中断，形成双侧神经瘤。我们的研究结果定义了一个病理序列，即缺乏迁移的神经内分泌GnRH细胞源于初级胚胎失败的外周嗅觉结构。这可以单独发生，如在孤立的KS中，或作为多效性疾病的一部分，如CHARGE综合征，13三体和18三体。
Patients with Kallmann syndrome (KS) have hypogonadotropic hypogonadism caused by a deficiency of gonadotropin-releasing hormone (GnRH) and a defective sense of smell related to olfactory bulb aplasia. Based on the findings in a fetus affected by the X chromosome-linked form of the disease, it has been suggested that hypogonadism in KS results from the failed embryonic migration of neuroendocrine GnRH1 cells from the nasal epithelium to the forebrain. We asked whether this singular observation might extend to other developmental disorders that also include arrhinencephaly. We therefore studied the location of GnRH1 cells in fetuses affected by different arrhinencephalic disorders, specifically X-linked KS, CHARGE syndrome, trisomy 13, and trisomy 18, using immunohistochemistry. Few or no neuroendocrine GnRH1 cells were detected in the preoptic and hypothalamic regions of all arrhinencephalic fetuses, whereas large numbers of these cells were present in control fetuses. In all arrhinencephalic fetuses, many GnRH1 cells were present in the frontonasal region, the first part of their migratory path, as were interrupted olfactory nerve fibers that formed bilateral neuromas. Our findings define a pathological sequence whereby a lack of migration of neuroendocrine GnRH cells stems from the primary embryonic failure of peripheral olfactory structures. This can occur either alone, as in isolated KS, or as part of a pleiotropic disease, such as CHARGE syndrome, trisomy 13, and trisomy 18.