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Neuronal Cell Types and Circuit Engineering - Previous and Current Research

Previously our focus was to study the human and mouse retina in health and disease. In a blinding disease called Retinitis pigmentosa, we repaired non-functional cone photoreceptors using optogenetics, specifically by expressing microbial Halorhodopsins, to restore visual function in mice. We further translated this approach to post mortem human retinas (Busskamp et al. 2010), which forms the basis for on-going clinical trials. Furthermore, our interest was to study basic functions of microRNAs in photoreceptors. We discovered that some of these non-coding RNAs had a high turnover in an activity-dependent manner (Krol et al. 2010). Upon cell type-specific knockout of the microRNA processing machinery, it turned out that a sensory-specific microRNA cluster maintains the structure of the light sensitive outer segments and the genetic identity of cone photoreceptors. Overexpression of this microRNA cluster in mouse embryonic stem cell-derived retinas resulted in the formation of outer segments that were sensitive to light (Busskamp et al. 2014).

Translating these approaches from mice to humans has been hindered by the lack of functional human neuronal tissues. This has prompted us to find novel routes to generate neurons from human induced pluripotent stem (iPS) cells. To this end, we explored the potency of transcription factors to induce neurogenesis in human iPS cells. The overexpression of two transcription factors resulted in the homogeneous differentiation of a bipolar neuronal cell type within four days. By capturing the coding and non-coding transcriptome, we aimed to identify the molecular routes for this rapid neurogenesis at the systems-level. In a second step we plan to use this knowledge to rationally engineer diverse neurons (Busskamp et al. 2014). Having succeeded with the generation of sets of different neurons, the next step is to assemble them into synthetic functional human neuronal circuits in vitro.

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