Suppression of β1-integrin in gonadotropin-releasing hormone cells disrupts migration and axonal extension resulting in severe reproductive alterations.
Suppression of β1-integrin in gonadotropin-releasing hormone cells disrupts migration and axonal extension resulting in severe reproductive alterations.
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DOI：
10.1523/jneurosci.3057-12.2012
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发表时间：
2012-11-21
期刊：
影响因子：
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通讯作者：
Giacobini P
中科院分区：
文献类型：
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作者：
Parkash J;Cimino I;Ferraris N;Casoni F;Wray S;Cappy H;Prevot V;Giacobini P
哺乳动物的生殖依赖于下丘脑神经元的功能，这些神经元的轴突投射到下丘脑正中隆起(ME)，在那里它们将促性腺激素释放激素(GnRH)释放到一个专门的毛细血管网络中，然后输送到垂体前叶。这些神经元在出生前起源于鼻胎盘，并沿着嗅犁鼻神经迁移到前脑。导致促性腺激素释放激素系统正确建立的复杂发育事件受到指导信号和细胞外基质分子特定的时空表达模式的严格调控，其功能部分是通过与含有β1亚单位的整合素结合而介导的。为了确定这些细胞表面蛋白在生殖中的生物学作用，利用Cre/loxP技术获得了GnRH神经元特异性β1-整合素条件性KO(GnRH-Itgb1−/−)小鼠。在这些小鼠中，β1整合素信号的丢失损害了GnRH神经元的迁移、它们的轴突延伸到ME、青春期开始的时间和生育能力。这些结果证实GnRH1-整合素基因参与了β系统的正常发育，并证明了该蛋白在获得雌性小鼠正常生殖能力方面的基础作用。
Reproduction in mammals is dependent on the function of hypothalamic neurons whose axons project to the hypothalamic median eminence (ME) where they release gonadotropin-releasing hormone (GnRH) into a specialized capillary network for delivery to the anterior pituitary. These neurons originate prenatally in the nasal placode and migrate into the forebrain along the olfactory-vomeronasal nerves. The complex developmental events leading to the correct establishment of the GnRH system are tightly regulated by the specific spatiotemporal expression patterns of guidance cues and extracellular matrix molecules, the functions of which, in part, are mediated by their binding to β1-subunit-containing integrins. To determine the biological role of these cell-surface proteins in reproduction, Cre/LoxP technology was used to generate GnRH neuron-specific β1-integrin conditional KO (GnRH-Itgb1−/−) mice. Loss of β1-integrin signaling impaired migration of GnRH neurons, their axonal extension to the ME, timing of pubertal onset, and fertility in these mice. These results identify β1-integrin as a gene involved in normal development of the GnRH system and demonstrate a fundamental role for this protein in acquisition of normal reproductive competence in female mice.