Forebrain gonadotropin-releasing hormone neuronal development: Insights from transgenic medaka and the relevance to X-linked Kallmann syndrome
Forebrain gonadotropin-releasing hormone neuronal development: Insights from transgenic medaka and the relevance to X-linked Kallmann syndrome
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DOI：
10.1210/en.2005-0468
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发表时间：
2006-03-01
期刊：
影响因子：
4.8
通讯作者：
Nagahama, Y
中科院分区：
文献类型：
--
作者：
Okubo, K;Sakai, F;Nagahama, Y
合成和释放GnRH的神经元对生殖的中枢调节至关重要。有证据表明前脑GnRH神经元起源于嗅板并迁移到其最终目的地，尽管这仍然是一个有争议的问题。X连锁Kallmann综合征（X-KS）的特征是继发于促性腺激素分泌不足的性腺功能衰竭，由KAL 1突变引起，KAL 1被认为调节前脑GnRH神经元的迁移。由于啮齿类动物基因组中缺乏Kal 1，而GnRH神经元分散在整个前脑中，因此前脑GnRH神经元的发育和X-KS的发病机制一直难以研究。在本研究中，我们产生了转基因青鳉，表达绿色荧光蛋白的控制下的gnrh 1和gnrh 3启动子分析前脑GnRH神经元的发育。我们的数据揭示了以下四个gnrh 1神经元群体的存在：一个嗅觉区域衍生的腹侧视前区人口，背侧视前区人口迁移的背侧端脑，内侧腹侧端脑人口迁移的前端脑，和一个nonmigrating腹侧下丘脑人口。我们发现，所有前脑gnrh 3神经元，从终端神经节延伸到中脑前部，从嗅觉区和三叉神经节神经元表达gnrh 3。在卵母细胞和早期胚胎中也观察到母体gnrh 3的表达。随后，我们确定了KAL 1的直系同源物和它的旁系同源形式的青鳉。与X-KS表型一致，青鳉KAL 1直系同源物的反义敲低导致前脑GnRH神经元迁移的破坏。因此，这些转基因青鳉为研究GnRH神经元发育和GnRH缺乏症提供了有用的模型系统。
Neurons that synthesize and release GnRH are essential for the central regulation of reproduction. Evidence suggests that forebrain GnRH neurons originate in the olfactory placode and migrate to their final destinations, although this is still a matter of controversy. X-linked Kallmann syndrome (X-KS), characterized by failed gonadal function secondary to deficient gonadotropin secretion, is caused by a mutation in KAL1, which is suggested to regulate the migration of forebrain GnRH neurons. Because rodents lack Kal1 in their genome and have GnRH neurons scattered throughout their forebrain, the development of forebrain GnRH neurons and the pathogenesis of X-KS have been difficult to study. In the present study, we generated transgenic medaka that expressed green fluorescent protein under the control of the gnrh1 and gnrh3 promoters for analyzing forebrain GnRH neuronal development. Our data revealed the presence of the following four gnrh1 neuronal populations: an olfactory region-derived ventral preoptic population, a dorsal preoptic population that migrates from the dorsal telencephalon, a medial ventral telencephalic population that migrates from the anterior telencephalon, and a nonmigratory ventral hypothalamic population. We found that all forebrain gnrh3 neurons, extending from the terminal nerve ganglion to the anterior mesencephalon, arise from the olfactory region and that trigeminal ganglion neurons express gnrh3. Maternal gnrh3 expression was also observed in oocytes and early embryos. We subsequently identified a KAL1 ortholog and its paralogous form in the medaka. Consistent with the X-KS phenotype, antisense knockdown of the medaka KAL1 ortholog resulted in the disruption of forebrain GnRH neuronal migration. Thus, these transgenic medaka provide a useful model system for studying GnRH neuronal development and disorders of GnRH deficiency.