An enormously complex part of the brain, the neocortex, is thought to give us the ability to generate conscious thought, develop language and perform complicated perception and spatial reasoning tasks. Understanding how the neocortex is built is key to understanding how our brain functions. Here, we propose to develop novel computational and experimental tools to help us understand how electrical activity and genetic circuits are coupled to generate the different cell types in this complex organ. While one might imagine an exceptionally elaborate network of genes giving rise to the brain, several reprogramming experiments suggest that just a handful developmentally important key factors control specific fate choices.
We aim to discover these sets of factors to build a coarse road map of the key gene expression events leading to the neocortex, and over lay on this map the expression patterns of all the other genes. We will do so using the data that has the spatial and temporal expression pattern of every mouse gene during the course of the development of the mouse brain from mid gestation to adult. We will develop a novel computational paradigm to analyze this data and extract the rules governing the construction of the neocortex. We will test these rules directly in an in vitro directed differentiation system, focusing on the pyramidal neurons. To enable such tests, we are developing ground-breaking imaging technologies to both measure and perturb gene expression and electrical activity in thousands of single cells as they differentiate in vitro from stem cells to post-mitotic pyramidal neurons. We will measure dynamics of candidate factors predicted by our computational analysis as well as calcium and electrical activity in single cells by using multiple fluorescent reporters. By analyzing these single cell time-series expression and activity data using a Bayesian statistical analysis and directly perturbing the dynamics of expression of specific genes and e

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
NIH Director’s Pioneer Award (NDPA) (DP1)
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Special Emphasis Panel (ZGM1-NDPA-A (01))
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Freund, Michelle
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Harvard University
Schools of Arts and Sciences
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Furchtgott, Leon A; Melton, Samuel; Menon, Vilas et al. (2017) Discovering sparse transcription factor codes for cell states and state transitions during development. Elife 6:
Close, Jennie L; Yao, Zizhen; Levi, Boaz P et al. (2017) Single-Cell Profiling of an In Vitro Model of Human Interneuron Development Reveals Temporal Dynamics of Cell Type Production and Maturation. Neuron 93:1035-1048.e5
Jang, Sumin; Choubey, Sandeep; Furchtgott, Leon et al. (2017) Dynamics of embryonic stem cell differentiation inferred from single-cell transcriptomics show a series of transitions through discrete cell states. Elife 6:
Yao, Zizhen; Mich, John K; Ku, Sherman et al. (2017) A Single-Cell Roadmap of Lineage Bifurcation in Human ESC Models of Embryonic Brain Development. Cell Stem Cell 20:120-134
Thomsen, Elliot R; Mich, John K; Yao, Zizhen et al. (2016) Fixed single-cell transcriptomic characterization of human radial glial diversity. Nat Methods 13:87-93
Kocabas, Askin; Shen, Ching-Han; Guo, Zengcai V et al. (2012) Controlling interneuron activity in Caenorhabditis elegans to evoke chemotactic behaviour. Nature 490:273-7
Thomson, Matt; Liu, Siyuan John; Zou, Ling-Nan et al. (2011) Pluripotency factors in embryonic stem cells regulate differentiation into germ layers. Cell 145:875-89