Defective gonadotropin-releasing hormone neuron migration in mice lacking SEMA3A signalling through NRP1 and NRP2: implications for the aetiology of hypogonadotropic hypogonadism
Defective gonadotropin-releasing hormone neuron migration in mice lacking SEMA3A signalling through NRP1 and NRP2: implications for the aetiology of hypogonadotropic hypogonadism
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DOI：
10.1093/hmg/ddq468
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发表时间：
2011-01-15
影响因子：
3.5
通讯作者：
Ruhrberg, Christiana
中科院分区：
文献类型：
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作者：
Cariboni, Anna;Davidson, Kathryn;Ruhrberg, Christiana
Kallmann综合征(KS)是一种遗传性疾病，以促性腺激素减退、性腺机能减退和嗅觉受损为特征。这种综合征的遗传原因目前仍不清楚，但被认为是由于促性腺激素释放激素(GnRH)神经元迁移过程中的发育缺陷。由于缺乏合适的小鼠模型，对这种疾病的病因的了解受到阻碍。促性腺激素释放激素神经元是下丘脑细胞，通过将促性腺激素释放激素十肽分泌到脑下垂体的门静脉血管来刺激促性腺激素的产生，从而集中控制哺乳动物的生殖。在发育过程中，这些细胞出生在脑外的鼻侧胎盘，并与嗅觉/犁鼻轴突一起迁移到前脑，并将自己定位于下丘脑。通过结合对转基因小鼠的分析和体外模型，我们在这里证明了3类信号素家族的分泌指导信号SEMA3A对于GnRH神经元系统的发展是必不可少的：SEMA3A信号的丢失改变了犁鼻神经的靶向和GnRH神经元向大脑的迁移，导致性腺尺寸缩小。我们发现SEMA3A通过其经典受体NRP(NRP)1和非常规的NRP2冗余地传递信号，而通常的NRP2配体SEMA3F对于这一过程是必不可少的。值得注意的是，通过Nrp1和NRP2缺乏SEMA3A或信号素信号的小鼠概括了迄今分析的单个KS病例的解剖特征，因此可用作阐明KS发病机制的遗传模型。
Kallmann syndrome (KS) is a genetic disease characterized by hypogonadotropic hypogonadism and impaired sense of smell. The genetic causes underlying this syndrome are still largely unknown, but are thought to be due to a developmental defect in the migration of gonadotropin-releasing hormone (GnRH) neurons. Understanding the causes of the disease is hampered by lack of appropriate mouse models. GnRH neurons are hypothalamic cells that centrally control reproduction in mammals by secreting the GnRH decapeptide into the portal blood vessels of the pituitary to stimulate the production of gonadotropins. During development, these cells are born in the nasal placode outside the brain and migrate in association with olfactory/vomeronasal axons to reach the forebrain and position themselves in the hypothalamus. By combining the analysis of genetically altered mice with in vitro models, we demonstrate here that a secreted guidance cue of the class 3 semaphorin family, SEMA3A, is essential for the development of the GnRH neuron system: loss of SEMA3A signalling alters the targeting of vomeronasal nerves and the migration of GnRH neurons into the brain, resulting in reduced gonadal size. We found that SEMA3A signals redundantly through both its classical receptors neuropilin (NRP) 1 and, unconventionally, NRP2, while the usual NRP2 ligand SEMA3F is dispensable for this process. Strikingly, mice lacking SEMA3A or semaphorin signalling through both NRP1 and NRP2 recapitulate the anatomical features of a single case of KS analysed so far, and may therefore be used as genetic models to elucidate the pathogenesis of KS.