Abstract
Global gene expression analysis of human embryonic stem cells (hESCs) that differentiate into neural cells would help to further define the molecular mechanisms involved in neurogenesis in humans. We performed a comprehensive transcripteome analysis of hESC differentiation at three different stages: early neural differentiation, neural ectoderm, and differentiated neurons. We identified and validated time-dependent gene expression patterns and showed that the gene expression patterns reflect early ESC differentiation. Sets of genes are induced in primary ectodermal lineages and then in differentiated neurons, constituting consecutive waves of known and novel genes. Pathway analysis revealed dynamic expression patterns of members of several signaling pathways, including NOTCH, mTOR and Toll like receptors (TLR), during neural differentiation. An interaction network analysis revealed that the TGFβ family of genes, including LEFTY1, ID1 and ID2, are possible key players in the proliferation and maintenance of neural ectoderm. Collectively, these results enhance our understanding of the molecular dynamics underlying neural commitment and differentiation.
Highlights
Embryonic stem cells (ESCs) are a promising tool for the study of neural development and cell lineage specification
Studies of the molecular mechanisms underlying the neural differentiation of human ESCs can help to unravel the complex gene pathways that are involved in neural cell commitment and differentiation processes
High throughput studies of gene expression have been applied to neural stem cells (NSCs) derived from the subventricular zone (SVZ) [1], NSCs derived from mouse ESCs and the fetal brain [2], dopaminergic neurons from mouse ESCs [3], heterogeneous neural cells from mouse ESCs [4] and neural progenitors (NPs) differentiated from mouse ESCs [5] and forebrain periventricular zone NPs compared to neuroectoderm from mESCs [6]
Summary
Embryonic stem cells (ESCs) are a promising tool for the study of neural development and cell lineage specification. The expression of several progenitor marker genes, including LMX1a, MSX1, ALDH1A1 (dopaminergic progenitors), SOX10 (oligodendroglial precursors) and PCP4 (Purkinje neuron protein), as well as genes involved in tight junctions among epithelial cells (AMOT), and proliferation of neural progenitors, such as WNT1 and WNT3a, were higher in NEs. Transcripts of genes involved in neural tube development and patterning, such as ALDH1A2, FOXA2, VANGL2, ZNF358, are among the genes that were up-regulated in NEs (Fig. 6B).
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