TY - JOUR
T1 - Repressor element 1 silencing transcription factor (REST) controls radial migration and temporal neuronal specification during neocortical development
AU - Mandel, Gail
AU - Fiondella, Christopher G.
AU - Covey, Matthew V.
AU - Lu, Diane D.
AU - LoTurco, Joseph J.
AU - Ballas, Nurit
PY - 2011/10/4
Y1 - 2011/10/4
N2 - Neurogenesis requires mechanisms that coordinate early cell-fate decisions, migration, and terminal differentiation. Here, we show that the transcriptional repressor, repressor element 1 silencing transcription factor (REST), regulates radial migration and the timing of neural progenitor differentiation during neocortical development, and that the regulation is contingent upon differential REST levels. Specifically, a sustained presence of REST blocks migration and greatly delays - but does not prevent - neuronal differentiation, resulting in a subcortical band heterotopia-like phenotype, reminiscent of loss of doublecortin. We further show that double-cortin is a direct gene target of REST, and that its overexpression rescues, at least in part, the aberrant phenotype caused by persistent presence of REST. Our studies support the view that the targeted down-regulation of REST to low levels in neural progenitors, and its subsequent disappearance during neurogenesis, is critical for timing the spatiotemporal transition of neural progenitor cells to neurons.
AB - Neurogenesis requires mechanisms that coordinate early cell-fate decisions, migration, and terminal differentiation. Here, we show that the transcriptional repressor, repressor element 1 silencing transcription factor (REST), regulates radial migration and the timing of neural progenitor differentiation during neocortical development, and that the regulation is contingent upon differential REST levels. Specifically, a sustained presence of REST blocks migration and greatly delays - but does not prevent - neuronal differentiation, resulting in a subcortical band heterotopia-like phenotype, reminiscent of loss of doublecortin. We further show that double-cortin is a direct gene target of REST, and that its overexpression rescues, at least in part, the aberrant phenotype caused by persistent presence of REST. Our studies support the view that the targeted down-regulation of REST to low levels in neural progenitors, and its subsequent disappearance during neurogenesis, is critical for timing the spatiotemporal transition of neural progenitor cells to neurons.
KW - In utero electroporation
KW - Neuronal cell fate
KW - Neuronal differentiation
UR - http://www.scopus.com/inward/record.url?scp=80053651936&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80053651936&partnerID=8YFLogxK
U2 - 10.1073/pnas.1113486108
DO - 10.1073/pnas.1113486108
M3 - Article
C2 - 21921234
AN - SCOPUS:80053651936
SN - 0027-8424
VL - 108
SP - 16789
EP - 16794
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 40
ER -