Shinya Yamamoto, D.V.M., Ph.D.
Department of Molecular and Human Genetics and
Program in Developmental Biology,
Drosophila genetics, whole-genome sequencing, notch signaling, dopamine signaling, novel disease gene discovery, cell-cell communication,
Many pediatric neurological diseases and conditions are caused by mutations found in the patients’ genomic DNA. Genetic mutations responsible for some of these disorders have been successfully identified (e.g. MECP2 in Rett Syndrome, SCA1 in Spinocerebellar Ataxia 1, FMR-1 in fragile X syndrome), which have opened up new doors for researchers to develop better diagnostic tools and new treatments. However for most neurological and psychiatric diseases, the causes are yet to be identified.
The human genome contains ~25,000 genes, yet the biological functions of more than 80% of them are not well characterized. Yamamoto lab aims to bridge this gap using powerful genetic tools available in the model organism, Drosophila melanogaster (fruit flies) that allow for rapid discovery and functional elucidation of genes that play key roles in the development and maintenance of nervous system. Using the information obtained from large-scale fly screens and combining this with large whole exome sequence (WES) datasets from thousands of patients with undiagnosed diseases (in collaboration with Drs. Jim Lupski, Richard Gibbs, Michael Wangler and the Baylor-Hopkins Center for Mendelian Genomics), we have identified a number of new human disease causing genes. Furthermore, by extensively studying the function of the fly homologs of these diseases genes, we have revealed molecular mechanisms by which mutations in these genes cause certain disease conditions.
We are especially interested in classes of genes that regulate cell-cell communication in development and disease. Notch signaling is a key pathway in the development of almost all organs, and defects in Notch signaling leads to different congenital disorders, stroke and cardiovascular diseases, as well as in many types of cancer in both children and adults. Dopamine signaling, on the other hand, regulates diverse aspects of neuronal function, and its dysfunction is seen in diverse neurodevelopmental (e.g. autism spectrum disorders, ADHD/ADD), neurological (e.g. dystonia, restless legs syndrome), psychiatric (e.g. schizophrenia, mood disorders, addiction), as well as neurodegenerative conditions (e.g. Parkinson’s disease). We aim to identify and characterize novel genes in these pathways and understand their precise functions in vivo using genetic, cell/molecular biological, biochemical, and electrophysiological methodologies. Our goal is to provide a better understanding of the molecular mechanisms underlying these diseases, allowing researchers to explore novel drug targets and potential therapies towards a cure.
1) Yamamoto S*, Jaiswal M*, Charng W-L, Gambin T, Karaca E, Mirzaa G, Wiszniewski W, Sandoval H, Haelterman, NA, Xiong B, Zhang K, Bayat V, David G, Li T, Chen K, Gala U, Harel T, Pehlivan D, Penney S, Vissers LELM, de Ligt J, Jhangiani S, Xie Y, Tsang SH, Parman Y, Sivaci M, Battaloglu E, Muzny D, Wan Y-W, Liu Z, Lin-Moore AT, Clark RD, Curry CJ, Schulze KL, Boerwinkle E, Dobyns WB, Allikmets R, Gibbs RA, Chen R, Lupski JR, Wangler MF, Bellen HJ (2014) A Drosophila genetic resource to study human disease genes and its use for gene discovery in human exome data. (*equal contribution). Cell, In press (September 25 issue).
2) Haelterman NA, Jiang L, Li Y, Bayat V, Sandoval H, Ugur B, Tan KL, Zhang K, Bei D, Xiong B, Charng W-L, Busby T, Jawaid A, David G, Jaiswal M, Venken KJT, Yamamoto S, Chen R, Bellen HJ (2014) Large-scale identification of chemically induced mutations in Drosophila melanogaster. Genome Research, In press.
3) Yamamoto S, Schulze KL, Bellen HJ (2014) Chapter 1: Introduction to Notch signaling. Methods in Molecular Biology: Notch Signaling, ed. Yamamoto S, Bellen HJ.
4) Wang S, Tan KL, Agosto MA, Xiong B, Yamamoto S, Sandoval H, Jaiswal M, Bayat V, Zhang K, Charng W-L, David G, Duraine L, Venkatachalam K, Wensel TG, Bellen HJ (2014) The retromer complex is required for rhodopsin recycling and its loss leads to photoreceptor degeneration. PLoS Biology, 12(4):e1001847.
5) Yamamoto S†, Seto ES (2014) Dopamine dynamics and signaling in Drosophila: an overview of genes, drugs and behavioral paradigms. Experimental Animals, 63(2):107-19. (†corresponding author) (Figure 1 was used as the cover image of this issue of the journal.).
6) CharngW-L, Yamamoto S, Bellen HJ (2014) Shared mechanisms between Drosophila peripheral nervous system development and human neurodegenerative diseases. Current Opinion in Neurobiology, 27:158-164.
7) Charng W.-L, Yamamoto S, Jaiswal M, Bayat V, Xiong B, Zhang K, Sandoval H, David G, Gibbs S, Lu H.-C, Chen K, Giagtzoglou N, Bellen HJ (2014) Drosophila Tempura, a novel protein prenyltransferase-alpha subunit, regulates Notch signaling via Rab1 and Rab11. PLoS Biology, 12(1): e1001777.
8) Yamamoto S, Bayat B, Bellen HJ, Tan C (2013) Protein Phosphatase 1ß limits ring canal constriction during Drosophila germline cyst formation. PLoS One, 8(7):e70502.
9) Giagtzoglou N, Li T, Yamamoto S, Bellen HJ (2013) dEHBP1 regulates Scabrous secretion during Notch mediated lateral inhibition. Journal of Cell Science, 126(Pt 16):3686-96.
10) Zhang K, Li Z, Jaiswal M, Bayat V, Xiong B, Sandoval H, Charng W-L, David D, Haueter C, Graham BH, Yamamoto S, Bellen HJ (2013) A complex of Sicily, the Drosophila homolog of Corf38, and Hsp90 binds and chaperones mitochondrial complex I subunits. Journal of Cell Biology, 200(6):807-20.