SOX2 reprograms resident astrocytes into neural progenitors in the adult brain.
Glial cells can be in vivo reprogrammed into functional neurons in the adult CNS; however, the process by which this reprogramming occurs is unclear. Here, we show that a distinct cellular sequence is involved in SOX2-driven in situ conversion of adult astrocytes to neurons. This includes ASCL1(+) neural progenitors and DCX(+) adult neuroblasts (iANBs) as intermediates. Importantly, ASCL1 is required, but not sufficient, for the robust generation of iANBs in the adult striatum. These progenitor-derived iANBs predominantly give rise to calretinin(+) interneurons when supplied with neurotrophic factors or the small-molecule valproic acid. Patch-clamp recordings from the induced neurons reveal subtype heterogeneity, though all are functionally mature, fire repetitive action potentials, and receive synaptic inputs. Together, these results show that SOX2-mediated in vivo reprogramming of astrocytes to neurons passes through proliferative intermediate progenitors, which may be exploited for regenerative medicine.
Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA.
Wenze
W
Niu
Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA.
Tong
T
Zang
Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA.
Derek K
DK
Smith
Department of Neuroscience, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA.
Tou Yia
TY
Vue
Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA.
Yuhua
Y
Zou
Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA.
Robert
R
Bachoo
Department of Neuroscience, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA.
Jane E
JE
Johnson
Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA. Electronic address: chun-li.zhang@utsouthwestern.edu.
Chun-Li
CL
Zhang
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D064032:Calbindin 2 / Q000378:metabolism; D065150:Cellular Reprogramming; D000089662:Doublecortin Protein; D007150:Immunohistochemistry; D007395:Interneurons / Q000166:cytology / Q000378:metabolism; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*
D051792:Basic Helix-Loop-Helix Proteins; D064032:Calbindin 2; D000089662:Doublecortin Protein; D055748:SOXB1 Transcription Factors; C499317:Ascl1 protein, mouse; C576511:Calb2 protein, mouse; C000714847:Dcx protein, mouse; C527783:Sox2 protein, mouse