Abstract
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.
Highlights
During mouse embryo development, the blastocyst differentiates into pluripotent primitive ectoderm and gives rise to a structure known as the epiblast [1]
Rest expression during neural stem cells (NSCs) and Neuron Development We investigated the role of Rest in neural development using an in-vitro Embryonic stem (ES) cell-derived neural differentiation model, which recapitulates events during neural development in vivo
ES cells firstly differentiate into neuroepithelial cells, which peak around 4–6 days of differentiation and express Sox1 and Nestin, and differentiate further into more restricted NSCs that peak around 10 days of differentiation and express either Ngn1 or Mash1 (Fig. 1C–D and Fig. S2B–C)
Summary
The blastocyst differentiates into pluripotent primitive ectoderm and gives rise to a structure known as the epiblast [1]. The ectoderm gives rise to the neuroectoderm in the form of a neural plate, which subsequently folds to generate the neural tube, composed of a single layer of neuroepithelial cells or neural stem cells (NSCs), where a series of ring-like constrictions mark the boundaries between the primordia of the major brain regions [3,4]. This process of neural development is orchestrated and accompanied by wholesale changes in transcriptional programmes and patterns of gene expression. We determine the function of Rest during neural development from ES cells through NSCs and neural progenitor cells (NPCs) to mature neurons using an in vitro ES cell-derived neural differentiation model
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