Deciphering the molecular landscape of intermediate states during direct neuronal reprogramming

• Applicant: Professorin Dr. Marisa Karow
• Subject Area: Developmental Neurobiology ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 426809158

Direct lineage reprogramming of somatic cells into induced neurons (iNs) has emerged as a novel promising strategy for brain repair. While it has been shown that direct reprogramming of brain-resident cells such as astrocytes and NG2 glia can be achieved even in vivo within the mouse brain, a major challenge represents the successful targeting and lineage conversion of human brain-resident cells. Furthermore, a major open question in the field concerns the nature of the intermediate states that are adopted during direct lineage reprogramming. The identification of the transcriptomic changes that underlie transcription factor-mediated direct reprogramming would immensely facilitate the identification of the cellular intermediates that drive the change in cell identity. The present proposal is based on own data that suggest the unfolding of a neural stem cell-like program during Ascl1 and Sox2 (AS)-mediated direct reprogramming of human brain pericytes into iNs. Here we aim at deciphering the molecular and cellular changes during pericyte-to-neuron conversion with a particular focus on genes that are transiently expressed during successful lineage conversion, referred to as switch genes. Specifically, we aim at i) dissecting the molecular changes in the transcriptional landscape along which pericyte convert into iNs, ii) characterizing the cellular features of cells on the trajectory to iNs, iii) functionally testing the role of genes dynamically regulated during reprogramming in the pericyte-to-iN conversion process, and iv) assessing whether switch genes are potentially relevant also during normal human neurogenesis. This study will not only provide fundamental insights into the molecular trajectory of direct neuronal reprogramming, but also provide new insights and tools to study the mechanisms underlying physiological neurogenesis in models of human brain development.

• DFG Programme: Research Grants