Researchers at the Institute of Molecular Genetics of the CNR of Pavia, IFOM and the Department of Biosciences of the University of Milan, have shown that the protein Nova2, until now considered only present in the brain, is also expressed by the cells of the blood vessels and is directly related to their development. The study, published in Nature Communications, was supported by AIRC - Associazione Italiana per la Ricerca sul Cancro.
The formation of new blood vessels, a process called angiogenesis, is required for the different tissues and organs of the organisms to receive oxygen and nutrients essential to their survival. However, this process is crucial also in tumor progression since, from the earliest stages of tumor development, cancer cells stimulate the formation of new blood vessels to support their growth and metastatic dissemination. In the last years, an explosion of interest in angiogenesis research has generated the necessary insights to develop the first clinically approved anti-angiogenic agents for cancer therapy. Unfortunately, they have showed limited efficacy.
Dr. Constanza Giampietro, Dr. Gianluca Deflorian and Dr. Stefania Gallo, researchers respectively of the University of Milan, IFOM of Milan and the Institute of Molecular Genetics of the National Research Council (IGM-CNR) of Pavia, and, led by Prof. Elisabetta Dejana and Dr. Claudia Ghigna, have shown that the Nova2 protein, which was previously considered to be neural cell-specific, is also expressed in the cells of the blood vessels.
"For the first time, our group has demonstrated that the alternative splicing" - a mechanism by which the bricks forming the human genes can be cut and pasted in many ways, allowing a single gene to produce different proteins - functions also during the development of the vascular system. Thanks to this process, Nova2 controls angiogenesis by expanding and manipulating the information stored in the genes and by deciding when, where and what types of proteins, but especially with that amount, must be synthesized" explains Dr. Ghigna.
"One of the most important findings arising from this collaboration - said Costanza Giampietro - is that the alternative splicing mechanism regulates the proper formation of the lumen of blood vessels during development."
"These in vitro observations - continues Gianluca Deflorian - have found an important confirmation in vivo in zebrafish, which constitutes a unique and powerful model to study vertebrate vascular development."
These findings show that alternative splicing is crucial for the development of our organism and for the regulation of its biological functions, as suggested by the sequencing of the human genome. Indeed, the human genome consists of about 20,000 genes, a similar number to that of much less complex organisms. Nonetheless, by using alternative splicing (a process much more abundant in human cells compared to less complex organisms) our cells produces almost 90,000 different types of protein allowing the development and the activity of the various tissues of our body.
"In addition, our studies have highlighted once again the significant similarities between the nervous and vascular systems. Both have specialized cells that use very similar molecular mechanisms to guide their movements through the surrounding tissue" says Dr. Ghigna.
These studies, supported by AIRC as well as other funding agencies, allowed a deeper understanding of the biological mechanisms that regulate the formation of new blood vessels. Alternative splicing is an essential process for tumor progression as it allows cancer cells to generate proteins not present in normal tissues. Thus, this discovery could provide important information regarding the pathogenesis of several human diseases, including cancer, to develop new and more specific therapeutic approaches for their treatment.
Article: The alternative splicing factor Nova2 regulates vascular development and lumen formation.
Giampietro C, Deflorian G, Gallo S, Di Matteo A, Pradella D, Bonomi S, Belloni E, Nyqvist D, Quaranta V, Confalonieri S, Bertalot G, Orsenigo F, Pisati F, Ferrero E, Biamonti G, Fredrickx E, Taveggia C, Wyatt CD, Irimia M, Di Fiore PP, Blencowe BJ, Dejana E, Ghigna C. The alternative splicing factor Nova2 regulates vascular development and lumen formation. Nat Commun. 2015; 6: 8479.
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