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Neuroscience Graduate Program at UCSF
Developmental and Molecular Mechansisms of Human Neurogenetic Diseases
Our laboratory has investigated the pathophysiology and genetic pathways important for lissencephaly and neuronal migration by producing and studying mouse models of human neuronal migration defects. We have helped to define the mechanism of action of genes responsible for human neuronal migration defects, determined components of the major pathways through which these genes act, and designed novel potential therapies for human patients using information from mutant mice. For example, we recently determined that LIS1 and NDEL1 coordinate the plus end directed transport of cytoplasmic dynein. We have used this information to devise a potential strategy for lissencephaly due to Lis1 haploinsufficiency. We found that cortical dynein localization can be rescued by inhibiting LIS1 degradation, and inhibiting LIS1 degradation can provide partial rescue of brain and behavioral phenotypes in vivo, supporting the notion that understanding the cellular mechanism of human disease genes can lead to novel therapeutic targets for even severe neurodevelopmental diseases.
Our laboratory was the first to produce mice with mutations in each of the three Dishevelled genes and they defined single, double and triple mutant phenotypes. We have used these mice to determine pathways important for these phenotypes, since Dishevelled participates in two conserved developmental pathways: the canonical Wnt pathway and the non-canonical planar cell polarity pathway. Of note, Dishevelled-1 (Dvl1) mutant mice were the first mice found to display mammalian social behavior defects, and are models for human neuropsychiatric diseases such as autism.
These studies have led his group to study human patients with autism under the hypothesis that autism may be the result of brain overgrowth due to problems with neurogenesis and/or neuronal migration. In addition to his basic research, Dr. Wynshaw-Boris heads an active clinical division of medical genetics.
1. Neuronal migration and neurogenesis in mouse models of human neuronal migration defects
2. In vivo functions of the mutlifunctional gene family Dishevelled in the brain during development and in the adult.
3. Neurobiological and genetic abnormlities important for the development of autism.
Postdoctoral Fellows:
Haim Belinson, PhD
Marina Bershteyn, PhD
Yuichiro Ihara, PhD
Jin Nakatani, PhD
Tiziano Pramparo, PhD
Kazuhito Toyo-oka, PhD
Yong Ha Youn, PhD
BMS Graduate Student:
Hyang-Mi “Amy” Moon
Technicians:
Lana Bogdanova
Jeehee Hong
Barlow, C., Hirotsune, S. Paylor, R., Liyanage, M. Eckhaus, M., Collins, F., Shiloh, Y., Crawley, J.N., Ried, T., Tagle, D. and Wynshaw-Boris, A. Atm-deficient mice: a paradigm of ataxia-telangiectasia. Cell. 1996; 86:159-171.
Lijam, N., Paylor, R., McDonald, M.P., Crawley, J.N., Deng, C-X., Herrup, K. Stevens, K.E., Macaferri. G., McBain, C.J., Sussman, D.J. and Wynshaw-Boris, A. Social interaction and sensorimotor gating abnormalities in mice lacking Dvl-1. Cell. 1997; 90:895-905.
Hirotsune, S., Fleck, M.W., Gambello, M.J., Bix, G.J., Chen, A., Clark, G.D., Ledbetter, D.H., McBain, C.J. and Wynshaw-Boris, A. Graded reduction of Pafah1b1 (Lis1) activity results in neuronal migration defects and early embryonic lethality. Nat Genet. 1998; 19:333-339.
Toyo-oka, K., Shionoya, A. Gambello, M.J., Cardoso, C., Leventer, R.J., Ward, H., Ayala, R., Tsai, L.H., Dobyns, W.B., Ledbetter, D.H., Hirotsune, S. and Wynshaw-Boris, A. 14-3-3ε is important for neuronal migration via binding to NUDEL: a molecular explanation for Miller-Dieker syndrome. Nature Genet. 2003; 34:274-285.
Wang, J., Zhang, X., Mark, S., Qian, D., Yoo, S., Radde-Gallwitz, K., Zhang, Y., Lin, X., Collazo, A., Wynshaw-Boris, A.* and Chen, P.* Regulation of polarized extension and planar cell polarity in the cochlea by the vertebrate PCP pathway. Nat Genet. 2005; 37:980-985. *co corresponding authors
Wang, J., Hamblet, N.S., Mark, S., Dickinson, M., Brinkman, B., Segil, N., Fraser, S.F., Chen, P., Wallingford, J.B. and Wynshaw-Boris, A. Dishevelled genes mediate a conserved mammalian PCP pathway to regulate convergent extension during neurulation. Development. 2006; 133: 1767-1778.
Yingling, Y., Youn, Y. H., Darling, D., Toyo-oka, K., Pramparo, T., Hirotsune, S. and Wynshaw-Boris, A. Neuroepithlial stem cell proliferation requires LIS1 for precise spindle orientation and symmetric division. Cell. 2008; 132: 474-486.
Yamada, M., Yoshida, Y., Mori, D., Takitoh, T., Kengaku, M., Takao, K., Miyakawa, T., Sato, M., Sorimachi, H., Wynshaw-Boris, A. and Hirotsune, S. Inhibition of calpain increases LIS1 and partially rescues in vivo phenotypes in a mouse model of lissencephaly. Nat Med. 2009; 15:1202-1208.
Hashimoto, M., Shinohara, K., Wang, J., Ikeuchi, S., Yoshiba, S., Meno, C., Nonaka, S., Takada, S., Hatta, K., Wynshaw-Boris, A.* and Hamada, H.* Planar polarization of node cells determines the rotational axis of the node cilia. Nat Cell Biol. 2010; 12:170-176. *co corresponding authors
Youn, Y.H., Pramparo, T., Hirotsune, S. and Wynshaw-Boris, A. Distinct dose-dependent neuronal migration defects in Lis1 and Ndel1 mutant mice. J Neuro. 2009; I29: 15520-15530.
Pramparo, T., Youn, Y.H., Yingling, J., Hirotsune, S. and Wynshaw-Boris, A. Novel embryonic neuronal migration and neurogenesis defects in Dcx mutant mice are exacerbated by Lis1 reduction. J Neuro. 2010; 30:3002-3012.
Hippenmeyer, S. Youn, Y.H., Moon, H.M., Miyamichi, K., Zong, H., Wynshaw-Boris, A. and Luo, L. Genetic mosaic dissection of Lis1 and Ndel1 during neuronal migration. Neuron. 2010; 68: 695-709.
Anthony Wynshaw-Boris, M.D./Ph.D.
Phone
415-476-5184
Physical address
513 Parnassus, HSE-901F
For internal campus mail
Box MC 0794
Other Websites
Biomedical Sciences Graduate Program
Developmental & Stem Cell Biology Graduate Program