How to Make a Neuron

Datum

20.03.2017

Zeit

11:00 - 12:00

Sprecher

Prof. Marius Wernig

Zugehörigkeit

Stanford University, School of Medicine

Serie

CMCB Life Sciences Seminar

Sprache

en

Hauptthema

Biologie

Andere Themen

Biologie, Medizin

Host

Volker Busskamp

Beschreibung

About the research of Prof. Wernig:Cellular differentiation and lineage commitment are considered robust and irreversible processes during development. Challenging this view, we found that expression of only three neural lineage-specific transcription factors Ascl1, Myt1l, and Brn2 could directly convert mouse fibroblasts into functional in vitro. These induced neuronal (iN) cells expressed multiple neuron-specific proteins, generated action potentials, and formed functional synapses. Thus, iN cells are bona fide functional neurons.Unlike reprogramming towards other lineages such as iPS cell reprogramming, the iN cell reprogramming process is very efficient (up to 20%) and deterministic. We previously found a molecular explanation in that Ascl1, a transcriptional activator, can access its physiological targets in fibroblasts even though these sites are in a closed chromatin state, thus robustly inducing a neuronal transcriptional program and rearranging the local chromatin. Surprisingly, Ascl1 alone is sufficient to induce fully functional iN cells, but in the majority of cells activates also non-neuronal programs. We further show, that Myt1l, a zinc finger domain protein, primarily functions as transcriptional repressor suppressing the fibroblast and other non-neuronal programs. This suggests that the physiological role of Myt1l is to ensure maintenance of neuronal identity by repressing many transcriptional program except neuronal genes, thereby functioning in exactly the inverse way as REST which blocks neuronal genes in many non-neuronal cell types. In summary, our data suggest that for optimal reprogramming results it may be important to use a combination of specific activators of the target cell program and specific repressors of the donor and other non-target cell programs.5 most important publications:1. Treutlein B, Lee QY, Camp JG, Mall M, Koh W, Shariati SA, Sim S, Neff NF, Skotheim JM, Wernig M*, Quake SR*. Dissecting direct reprogramming from fibroblast to neuron using single-cell RNA-seq. Nature. 2016 Jun 8;534(7607):391-5.* co-corresponding authors Lujan E, Zunder ER, Ng YH, Goronzy IN, Nolan GP, Wernig M. Early reprogramming regulators identified by prospective isolation and mass cytometry. Nature. 2015 May 21; 521(7552): 352-6.3. Sebastiano V, Zhen HH, Haddad B, Bashkirova E, Melo SP, Wang P, Leung TL, Siprashvili Z, Tichy A, Li J, Ameen M, Hawkins J, Lee S, Li L, Schwertschkow A, Bauer G, Lisowski L, Kay MA, Kim SK, Lane AT, Wernig M*, Oro AE*. Human COL7A1-corrected induced pluripotent stem cells for the treatment of recessive dystrophic epidermolysis bullosa. Sci Transl Med. 2014 Nov 26;6(264):264ra163* co-corresponding authors4. Wapinski OL, T Vierbuchen, K Qu, QY Lee, S Chanda, DR Fuentes, PG Giresi, YH Ng, S Marro, NF. Neff, D Drechsel, B Martynoga, D Castro, AE Webb, A Brunet, F Guillemot, HY Chang, and Wernig M. Hierarchical mechanisms for transcription factor-mediated reprogramming of fibroblasts to neurons. Cell 2013 Oct. 24; 155(3): 621-635. 10.1016/j.cell.2013.09.028 Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Südhof TC, Wernig M. (2010). Direct conversion of fibroblasts to functional neurons by defined factors. Nature. Jan 27.

Links

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Letztmalig verändert: 20.03.2017, 08:54:04