Alysson Muotri is broadly interested in how human cognitive diversity relates to insertions of mobile genetic elements. That these are linked at all is a novel idea; such insertions have traditionally been thought to happen only in germ and stem cells. In contrast, his work has shown that one of these elements, LINE-1 retrotransposons, which compose ~20% of the human genome, are expressed in somatic cells during development, especially neurons. Because these insertions can disrupt or significantly alter expression of genes important to neuronal function, the resulting genetic mosaicism could lead to differences among individuals in network connectivity.
Autism spectrum disorders are known to involve changes in network connectivity, so Muotri’s group is studying neuronal development in these disorders, both in mouse models and in neurons cultured from patients’ cells. They’ve begun this work in Rett syndrome, a rare X-linked genetic disorder that shares clinical features with autism because it is genetically simpler. Their recent finding that L1 elements retrotranspose more often both in a mouse model of Rett syndrome, which doesn’t express methyl-CpG-binding protein 2 (MeCP2), and in neural precursor cells derived from Rett patient fibroblasts, suggests that differences in neural development may result from genomic changes.
To develop a model that more closely relates to the human disorder, the Muotri lab fully characterized neurons cultured from Rett patient induced pluripotent stem cells (iPSCs), and found that Rett neurons develop significantly fewer synaptic connections and are less electrically active. They now explore how these differences could work as read outs on drug-screening platforms. The Muotri lab is also more broadly interested in using iPSCs to understand neuronal development in neurological and psychiatric disorders. They became involved with CNME to explore how layered culture scaffolds could be used to culture neurons in three dimensions.
- Department of Pediatrics
- Department of Cellular and Molecular Medicine
- Lab website
Griesi-Oliveira K, Acab A, Gupta AR, Sunaga DY, Chailangkarn T, Nicol X, Nunez Y, Walker MF, Murdoch JD, Sanders SJ, Fernandez TV, Ji W, Lifton RP, Vadasz E, Dietrich A, Pradhan D, Song H, Ming GL, Gu X, Haddad G, Marchetto MC, Spitzer N, Passos-Bueno MR, State MW, Muotri AR. Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons. Mol Psychiatry 2014; published online Nov 11.
Gage FH, Muotri AR. What makes each brain unique. Sci Am. 2012; 306 (3): 26-31.
Marchetto MCN, Carromeu C, Acab A, Yu D, Yeo GW, Mu Y, Chen G, Gage FH, Muotri AR. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells Cell 2010; 143 (4): 527-539.