Biology of immunoglobulin superfamily, member 1 (IGSF1)

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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.