Biology of immunoglobulin superfamily, member 1 (IGSF1)

基因组中大约有2万到2.5万个基因；然而，这个数字大大低估了人类可以合成的蛋白质的复杂性和多样性。现在已经确定，单个基因可以通过多种机制产生多种蛋白质产物，包括产生替代蛋白质编码信使RNA分子和蛋白质合成后的修饰（所谓的翻译后加工）。在我们对抑制素（控制垂体激素合成的性腺蛋白）的假定受体的分析中，我们发现了免疫球蛋白超家族成员1 （IGSF1）。这种基因在中枢神经系统（CNS）和脑垂体前叶中特别活跃。有趣的是，IGSF1基因以多种方式产生至少四种不同的蛋白质形式。我们克隆、鉴定并敲除小鼠的Igsf1基因，以确定其在垂体和中枢神经系统功能中的作用。令人惊讶的是，缺乏这种基因的老鼠表现正常。我们随后的分析阐明了这一发现。在突变小鼠中，四种IGSF1形式中的三种被成功地删除，但第四种仍保持在正常小鼠中观察到的水平。这是至关重要的，因为form 4在中枢神经系统中特别丰富。此外，我们现在已经观察到，在脑垂体中最丰富的形式1蛋白质，其加工方式使其与形式4无法区分。因此，我们预测突变小鼠中形式4的保留可以弥补其他三种蛋白质形式的损失。在本申请中，我们提出了两套实验方法来了解更多关于IGSF1的生物学，以确定该基因及其各种蛋白产物的功能。最终，这些研究将使我们更彻底地了解细胞从相同的潜在基因序列中产生多种蛋白质的机制的多样性。

There are approximately 20,000-25,000 genes in the genome; however, this number dramatically underestimates the complexity and diversity of proteins that can be synthesized in humans. It is now well-established that individual genes can give rise to multiple protein products through a variety of mechanisms, including generation of alternative protein-encoding messenger RNA molecules and modification of proteins following their synthesis (so-called post-translational processing).  In our analysis of putative receptors for inhibins, gonadal proteins that control pituitary hormone synthesis, we uncovered immunoglobulin superfamily, member 1 (IGSF1).  This gene is particularly active in the central nervous system (CNS) and anterior pituitary gland.  Intriguingly, the IGSF1 gene generates at least four different protein forms in a variety of ways. We cloned, characterized and knocked out the Igsf1 gene in mice in an effort to determine its roles in pituitary and CNS function. Surprisingly, mice lacking the gene appeared normal. Our subsequent analyses shed light on this finding. Three of the four IGSF1 forms were successfully deleted in the mutant mice, but the fourth remained at levels observed in normal mice. This is critical because form 4 is particularly abundant in the CNS.  In addition, we have now observed that the form 1 protein, which is the most abundant type in the pituitary, is processed in a manner that renders it indistinguishable from form 4. Therefore, we predict that retention of form 4 in mutant mice can compensate for the loss of the other three protein forms. In this application, we propose two sets of experimental approaches to learn more about the biology of IGSF1 with the long-term objective of determining the function of this gene and its various protein products. Ultimately, these studies will give us a more thorough appreciation of the diversity of mechanisms cells can use to generate multiple proteins from the same underlying genetic sequence.