Reprogramming of fibroblasts to a neural fate
- Thomas Scott Vierbuchen.
- Sept. 2012.
- Physical description
- online resource (vii, 192 pages) : illustrations (some color)
- Vierbuchen, Thomas Scott.
- Beachy, Philip Arden. thesis advisor.
- Chang, Howard Y. (Howard Yuan-Hao), 1972- thesis advisor.
- Wernig, Marius. thesis advisor (primary).
- Wysocka, Joanna, Ph. D. thesis advisor.
- Stanford University. Program in Cancer Biology.
- Stanford University. Committee on Graduate Studies. degree grantor.
- Includes bibliographical references (p. 153-192).
- Cellular differentiation and lineage commitment are considered to be robust and irreversible processes during development. However, recent work has shown that mouse and human fibroblasts can be reprogrammed to a pluripotent state with a combination of four transcription factors. This raised the question of whether transcription factors could directly induce other defined somatic cell fates, and not only an undifferentiated state. We hypothesized that combinatorial expression of neural-lineage-specific transcription factors could directly convert fibroblasts into neurons. Starting from a pool of nineteen candidate genes, we identified a combination of only three factors, Ascl1, Brn2 (also called Pou3f2) and Myt1l that suffice to rapidly and efficiently convert mouse embryonic and postnatal fibroblasts into functional neurons in vitro. These induced neuronal (iN) cells express multiple neuron-specific proteins, generate action potentials and form functional synapses. Similar methods can also convert human fibroblasts to functional iN cells, by forced expression of Ascl1, Brn2, Myt1l and NeuroD1. Generation of iN cells from non-neural lineages could have important implications for studies of neural development, neurological disease modelling and regenerative medicine.
- Publication date
- Submitted to the Program in Cancer Biology and the Committee on Graduate Studies of Stanford University.
- Thesis (Ph.D.)--Stanford University, 2012.