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Ribosome Biogenesis and Disease

It has been established that several different genes involved in the ribosome biogenesis process are linked to growth defects and diseases in both humans and in animal models.  One example is the mutation of several different ribosomal protein (rp) genes. In humans the mutation of several different rp genes can lead to hematopoetic cell loss in the bone marrow failure disorders Diamond-Blackfan anemia (DBA) or myeloid dysplasia (MDS), and in zebrafish can lead to the formation of highly invasive and lethal tumors.  The mutation of other genes involved in ribosome biogenesis, such as dyskerin, nhp2, or nop10 are linked to another bone marrow failure disorder, dyskeratosis congenita (DC). Interestingly, all these diseases, DBA, MDS, and DC, in addition to leading to the development of bone marrow failure also predispose individuals to acute myeloid leukemia (AML).

We have previously shown that tumor cells derived from zebrafish carrying rp mutations are impaired in their ability to translate the tumor suppressor p53 mRNA.  One area of research therefore in the lab is to determine on a global scale what other mRNAs may be affected by rp loss, and how these losses may contribute to malignancy.  These studies utilize polysomal transcriptome profiling of both tumors derived from zebrafish as well as human cells from DBA patients.

Another area of research is to use zebrafish embryos carrying mutations in ribosome biogenesis genes to study alterations of pathways known to affect the development of hematopoetic stem cells (HSCs).  In addition to studying the p53 pathway we are also interested in another well studied pathway in the development of HSCs, the Notch pathway (which has also been shown to be critically important for neurogenesis). 

Finally, we are interested in secondary mutations that drive tumor formation in rp mutant zebrafish.  It is highly counter-intuitive that a mutation resulting in a growth defect and impairment of translation would lead to cancer, since by definition translation in cancer cells occurs at a very high rate and growth is out of control.  Therefore there must be some molecular switch that occurs in order for translation impaired cells to become tumor cells.  To address this problem we are performing exome sequencing of tumor cells with rp mutations to determine which secondary mutations may be assisting the cells to overcome the growth defect and translation impairment.

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image description
Expression of neurogenin-1, a Notch pathway gene, in wild type zebrafish embryos
Staining of red blood cells in wild type (top) and nop10-/- (bottom) zebrafish embryos
Staining of red blood cells in wild type (top) and nop10-/- mutant (bottom) zebrafish embryos