Hu proteins, a novel family of neuron-specific regulators for post-transcriptional RNA processing.

摘要

Alternative splicing is a general mechanism in higher eukaryotic organisms used to increase the diversity of proteome. In contrast to its importance, the mechanism of alternative splicing regulation is not well understood. In the nervous system where extensive alternative splicing occurs, thousands of genes have neuron-specific isoforms, indicating that alternative splicing plays a specifically important role in neuronal function. To date, only a few neuronal splicing factors have been identified and a small number of genes that undergo neuron-specific splicing have been studied.; During my Ph.D. study, I identified a family of novel neuron-specific splicing regulators, Hu proteins (including HuR, HuB, HuC, and HuD in humans). Hu proteins have been shown to regulate neuronal differentiation. My studies provided solid evidence that support the splicing regulatory function of Hu proteins. Two genes that undergo neuron-specific splicing were used as model systems in my research: calcitonin/CGRP and NF1 exon.; The calcitonin/CGRP gene was one of the earliest genes shown to undergo alternative splicing. My research using this model system indicated two mechanisms whereby Hu proteins inhibit the recognition of the non-neuronal exon: blocking the positive function of splicing factors TIA-1 and TIAR and suppressing polyadenylation.; NF1 is a well-studied tumor suppressor and functions as a ras signaling pathway modulator. The neuron-specific skipping of exon 23a has been reported to change its activity in regulating ras, but how this splicing event is regulated in neurons was not known. My research demonstrated that Hu proteins are strong regulators in neurons that suppress recognition of exon 23a by the splicing machinery.; In addition, my studies implicated a role for other splicing factors in regulating the neuron-specific splicing of NF1. In addition to the two model systems, I also studied the different activities of individual Hu proteins in splicing regulation. This finding revealed functional differences between individual Hu proteins for the first time and raised an interesting issue of their differential roles in regulating neuronal differentiation.; In summary, my research has contributed significantly to the understanding of the neuron-specific splicing regulation. It also provides a foundation for future investigations.