Dr. Alysson  Muotri, Ph.D.

Associate Professor
Director of the Stem Cell Program
Institute for Genomic Medicine
Dept. of Pediatrics & Cellular Molecular Medicine 
UCSD School of Medicine, CA

Hangout Title: "Modeling neurodevelomental disorders with stem cells and brain organoids”
Hangout Schedule: July 3rd: 9.00 am PST, 11 am CST, 12 pm EST, 9.30 pm IST

 


Dr. Muotri earned a BSc in Biological Sciences from the State University of Campinas in 1995 and a Ph.D. in Genetics in 2001 from University of Sao Paulo, in Brazil. He moved to the Salk Institute as Pew Latin America Fellow in 2002 for a postdoctoral training in the fields of neuroscience and stem cell biology. He has been a Professor at the School of Medicine, University of California in San Diego since 2008. His research focuses on modeling neurological diseases, such as Autism Spectrum Disorders, using human induced pluripotent stem cells. His lab has developed several techniques to culture human neurons and glia for basic research and drug-screening platforms. He has received several awards, including the prestigious NIH Director’s New Innovator Award, NARSAD, Emerald Foundation Young Investigator Award, Surugadai Award from Tokyo University, Rock Star of Innovation from CONNECT, NIH EUREKA Award among others.

Publications

Chailangkarn, T., Trujillo, C.A., Freitas, B.C., Hrvoj-Mihic, B., Herai, R.H., Yu, D.X., Brown, T.T., Marchetto, M.C.N., Bardy, C., McHenry, L., Stefanacci, L., Jarvinen, A., Searchy, Y.M., DeWitt, M., Wong, W., Lai, P., Ard, M.C., Hanson, K.L., Romero, S., Jacobs, B., Dale, A.M., Dai, L., Korenberg, J.R., Bellugi, U., Gage, F.H., Halgren, E., Semendeferi, K. & Muotri, A. R. A human neurodevelopmental model for Williams syndrome. Nature (2016). In Press.

This publication describe a human model for Williams syndrome (WS) using iPSC. People affected by WS have a hyper social phenotype but the genes related to this behavior are unknown. We postulated that one of the genes in the WS deletion region, FZD9, could be implicated in the phenotype. Cortical progenitor cells from WS individuals have a high level of apoptosis compared to controls. We showed that FZD9 is responsible for this observation. The progenitor cells that survive form cortical neurons from layer V/VI that are far more complex than controls. WS networks is also more active and with early burst synchronization. We validate these observations by MRI and showed that WS subjects have reduced cortical surface. We also validated the morphometric observations from the iPSC in postmortem tissues. Our data indicates a strong cell autonomous neuronal phenotype that is kept during WS neurodevelopment. This is the first work where iPSC were used to generate insights about a neurodevelopmental disorder and will help us to understand the molecular and cellular basis of the human social brain capacity.


Marchetto, M.C.N., Belinson, H., Tian, Y., Freitas, B.C., Fu, C., Vadodaria, K., Beltrao-Braga, P., Trujillo, C.A., Mendes, A.P.D., Padmanabhan, K., Nunez, Y., Ou, J., Ghosh, H., Wright, R., Brennand, K., Pierce, K., Eichenfield, L., Prampano, T., Eyler, L., Barnes, C.C., Courchesne, E., Geschwind, D.H., Gage, F.H., Wynshaw-Boris, A., Muotri, A.R. Altered proliferation and networks in neural cells derived from idiopathic autistic individuals. Mol. Psy. (2016). In Press.

This publication reports a model of idiopathic autism using reprogrammed cells from autistic individuals with enlarged brains. Our genome sequencing data showed that some of these patients carry genetic mutation related to cell cycle. In fact, we do detect a fast proliferation on the neural progenitor cells that might explain the big brain phenotype in this subgroup. Moreover, neurons derived from the iPSC have clear altered synaptogenesis leading to defects in network synchronization. Our gene expression analyses pointed to misregulated pathways in neurotransmitters that could be potential therapeutic targets. Finally, we use the system to study the drug response from these networks. IGF-1, a candidate drug current in clinical trials for autism, showed promising network rescue capacity. We also observed a differential individual response to IGF-1, suggesting that our platform could be used to stratify the autistic population for clinical trials.


Cugola, F.R., Fernandes, I.R., Russo, F.B., Freitas, B.C., Dias, J.L.M., Guimaraes, K.P., Benazzato, C., Almeida, N., Pignatari, G.C., Romero, S., Polonio, C.M., Cunha, I., Freitas, C.L., Brandao, W.N., Rossato, C., Andrade, D.G., Faria, D.P., Garcez, A.T., Buchpigel, C.A., Braconi, C.T., Mendes, E., Sall, A.A., Zanotto, P.M.A., Peron, J.P.S., Muotri, A.R.*, Beltrao-Braga, P.* The Brazilian Zika virus causes birth defects in experimental models. Nature 534: 267-71 (2016). *co-corresponding authors.

In this publication, we report a causal link between the circulating Brazilian Zika strain and birth defects. This could be accomplished by isolating the potential causative agent (the Brazilian Zika virus) from a microcephalic case and testing the impact of the infection in several models. In mice, we showed that the virus can cross the placenta and infect the developing fetus. Animals were born with severe growth arrest and signs of microcephaly, such as neuronal death and cortical reduction. We also use human stem cells to generate cerebral organoids to test the impact of two different Zika viruses. In side-by-side tests, we noticed that the recent mutated Brazilian virus could dramatically impact the proliferative zones, causing cell death and reducing the population of subtypes of cortical neurons. The zoonotic African MR766 strain was less active in human cells, but did induced cell death in neural cells derived from non-human primates.


Griesi-Oliveira, K., Acab, A., Gupta, A., Sunaa, D. Chailangkarn, T., Nicol, X., Nunez, Y., Walker, M., Murdoch, Jo., Sanders, S., Fernandez, T., Ji, W., Lifton, R., Vadasz, E., Dietrich, A., Pradhan, D., Song, H., Ming, G., Guoe, X., Haddad, G., Marchetto, M., Sptzer, N., Passos-Bueno, M., State, M. & Muotri, A.R. Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons. Mol. Psychiatry 20: 1350-65. (2015). 

This publication shows, for the first time, that is possible to model sporadic autism using iPSCs. To collect large samples from families, we create the Tooth Fairy collection program. Families send the deciduous tooth to the lab where we use the dental pulp cells as a source for our reprogramming studies. On this paper, we demonstrate that the combination of genomics and stem modeling can reveal novel genes implicated in autism, common molecular pathways affected in different types of autism and the possibility of personalized medicine.


Marchetto, M. C. N., Carromeu, C., Acab, A., Yu, D., Yeo, G., Yangling, M., Gage, F. H. & Muotri, A. R. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell, 143(4): 527-39 (2010).

This publication is a comprehensive analysis of iPSC derived neurons from Rett syndrome patients, revealing new insights about the disease and proposing reversion of human neurons as read outs for a drug screening platform. It is one of the fist disease-in-a-dish papers published and key findings was already replicated by several independent laboratories.