Research

Molecular mechanism of RNA splicing and human diseases caused by aberrant RNA splicing

RNA splicing is a fundamental regulatory mechanism for eukaryotic gene expression. Studies have identified hundreds of splicing factors to date. However it remains to be understood how these splicing factors function and interact in vivo. From a suppressor screen, we identified several mutations in genes that encode the C. elegans orthologs of two key splicing factors, the U2AF large subunit (UAF-1) and SF1/BBP (SFA-1). Using a microarray-based screen to analyze gene expression in uaf-1(n4588) mutants, we identified an endogenous splicing reporter gene, tos-1. We also cloned and identified a highly conserved novel splicing factor gene, mfap-1. Our results provide in vivo evidence that these splicing factors regulate alternative splicing.

Mutations in RNA splicing factors could lead to severe diseases, which include spinal muscular atrophy (SMA) and retinitis pigmentosa (RP). Using genetic tools we established for studying the in vivo regulation of RNA splicing, we found that the C. elegans SMA-related gene smn-1, RP-related gene prp-8 and a tumor suppressor-related gene T08B2.5 all interact with the U2AF large subunit gene uaf-1, providing new approaches for studying the in vivo functions of these genes.

Mouse Model of Parkinson disease related gene LRRK2: gene function study

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders. PD is primarily characterized by the loss of dopamine (DA) neurons in the substantia nigra and the development of proteinacious neuronal inclusions called Lewy bodies. Several genes including a-synuclein, PARKIN, Pink1, DJ-1, and most common gene LRRK2 have been implicated in familial PD. To date, many genetic mouse models of PD have been generated but most failed to mimic the pathology of nigrostriatal system. Here, we sought to study the effects of LRRK2 on peripheral organs as an alternative approach to understanding the molecular functions of LRRK2 in PD. In a LRRK2 knockout line, we found that mice older than 18 months could develop hepatic vascular growths similar to hemangiomas. We suggest this phenotype is related to LRRK2 function in kidney. Meanwhile, we have generated double knockout mice to investigate the interaction between LRRK2 and other PD genes.

The molecular, genetic and neural mechanisms of animal behaviors

Methyl salicylate (MeSa) is a volatile stress hormone released by plants when infected by pathogens or attacked by herbivores. Besides enhancing the systemic acquired resistance of the affected plants, MeSa could be sensed by adjacent plants as a warning signal for the infection. Ecological experiments also uncovered interesting effects of MeSa on animal behaviors. However it is not clear what molecules and neural mechanisms determine whether an animal is attracted to or repelled by MeSa. We found that C.elegans strongly avoids MeSa. Four conserved genes related to the sodium leak channel NALCN were found to affect C. elegans avoidance to MeSa. In humans mutations in the NALCN channel could cause a wide variety of diseases. By studying the functions and interactions of these genes, we hope to understand the molecular and neural mechanisms of C.elegans avoidance behavior to MeSa and gain new insights into the pathogenesis NALCN-related diseases.

Iodine and ROS homeostasis

Reactive oxygen species (ROS) play key roles in the regulation of fundamental biological processes. Dysregulation of ROS homeostasis underlies multiple diseases. In recent years excess iodide intake has been identified to be a major causal factor of different thyroidal diseases, the mechanisms of which remain elusive. By studying the biological effects of excess iodide on C. elegans, we identified five conserved genes that are regulators of ROS biogenesis and homeostasis. Mutations in these genes could make animals survive in excess iodide. We hypothesize that the biological effects of excess iodide intake are closely related to the regulation of ROS homeostasis. We will study the functions and interactions of these genes and identify new genes that affect the biological effects of iodide in C. elegans. Our study will provide new insights into the regulation of ROS homeostasis and the molecular mechanism underlying excess iodide-related diseases.