Biology of immunoglobulin superfamily, member 1 (IGSF1)

基因组中大约有20,000-25,000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。现在公认的是，单个基因可以通过各种机制产生多种蛋白质产物，包括生成替代的蛋白质编码信使RNA分子和蛋白质合成后的修饰(所谓的翻译后处理)。在我们对抑制素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)。免疫球蛋白超家族成员1(IGSF1)控制着脑下垂体激素的合成。有趣的是，IGSF1基因以各种方式产生至少四种不同的蛋白质形式。我们在小鼠中克隆、鉴定并敲除了Igsf1基因，试图确定它在脑垂体和中枢神经系统功能中的作用。令人惊讶的是，缺乏该基因的小鼠看起来很正常。我们随后的分析揭示了这一发现。四种IGSF1形式中的三种在突变小鼠中被成功删除，但第四种形式在正常小鼠中保持在观察到的水平。这一点至关重要，因为形式4在中枢神经系统中特别丰富。此外，我们现在观察到，形式1是脑下垂体中含量最丰富的类型，其处理方式使其与形式4无法区分。因此，我们预测，在突变小鼠中保留形式4可以弥补其他三种蛋白形式的损失。在这一应用中，我们提出了两套实验方法来更多地了解IGSF1的生物学，并以确定该基因及其各种蛋白质产物的功能为长期目标。最终，这些研究将让我们更彻底地了解细胞可以用来从相同的潜在基因序列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.