Rest-mediated regulation of extracellular matrix is crucial for neural development.
Neural development from blastocysts is strictly controlled by intricate transcriptional programmes that initiate the down-regulation of pluripotent genes, Oct4, Nanog and Rex1 in blastocysts followed by up-regulation of lineage-specific genes as neural development proceeds. Here, we demonstrate that the expression pattern of the transcription factor Rest mirrors those of pluripotent genes during neural development from embryonic stem (ES) cells and an early abrogation of Rest in ES cells using a combination of gene targeting and RNAi approaches causes defects in this process. Specifically, Rest ablation does not alter ES cell pluripotency, but impedes the production of Nestin(+) neural stem cells, neural progenitor cells and neurons, and results in defective adhesion, decrease in cell proliferation, increase in cell death and neuronal phenotypic defects typified by a reduction in migration and neurite elaboration. We also show that these Rest-null phenotypes are due to the dysregulation of its direct or indirect target genes, Lama1, Lamb1, Lamc1 and Lama2 and that these aberrant phenotypes can be rescued by laminins.
Sun
Yuh-Man
YM
Centre for the Cellular Basis of Behaviour, The James Black Centre, Institute of Psychiatry, King's College London, London, UK. yuh-man.sun@iop.kcl.ac.uk
Cooper
Megan
M
Finch
Sophie
S
Lin
Hsuan-Hwai
HH
Chen
Zhou-Feng
ZF
Williams
Brenda P
BP
Buckley
Noel J
NJ
D000818:Animals; D001755:Blastocyst / Q000166:cytology*; D018929:Cell Culture Techniques / Q000295:instrumentation; D002468:Cell Physiological Phenomena / Q000187:drug effects; D002478:Cells, Cultured / Q000502:physiology; D005109:Extracellular Matrix / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D018390:Gene Targeting; D007797:Laminin / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016501:Neurites / Q000648:ultrastructure; D009474:Neurons / Q000166:cytology; D054261:Neurulation / Q000235:genetics / Q000502:physiology*; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects; D034622:RNA Interference; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000099229:RE1-Silencing Transcription Factor
D016326:Extracellular Matrix Proteins; D007797:Laminin; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor; C498522:Lamc2 protein, mouse; C102645:laminin alpha 2; C089141:laminin gamma 1; C084098:laminin A