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Tlx3 exerts context-dependent transcriptional regulation and promotes neuronal differentiation from embryonic stem cells.

ABSTRACT: The T cell leukemia 3 (Tlx3) gene has been implicated in specification of glutamatergic sensory neurons in the spinal cord. In cranial sensory ganglia, Tlx3 is highly expressed in differentiating neurons during early embryogenesis. To study a role of Tlx3 during neural differentiation, mouse embryonic stem (ES) cells were transfected with a Tlx3 expression vector. ES cells stably expressing Tlx3 were grown in the presence or absence of a neural induction medium. In undifferentiated ES cells, there was no significant difference in gene expression in the presence or absence of Tlx3, even after ES cells were cultured for an extensive time period. In contrast, expression levels of Mash1, Ngn1, and NeuroD were significantly higher in Tlx3-expressing cells after neural induction for 4 days compared with those in cells expressing the control vector. At 7 days after neural induction, whereas expression of the proneural genes was down-regulated, VGLUT2, GluR2, and GluR4 were significantly increased in ES cell-derived neurons expressing Tlx3. The sequential and coordinated expression of the proneural and neuronal subtype-specific genes identifies Tlx3 as a selector gene in ES cells undergoing neural differentiation. In addition, the differential effects of Tlx3 overexpression in undifferentiated ES cells compared with ES cell-derived neurons suggest that Tlx3 exerts context-dependent transcriptional signals on its downstream target genes. The context-dependent function of Tlx3 as a selector gene may be used to establish a novel strategy to conditionally generate excitatory glutamatergic neurons from ES cells to cure various types of neurodegenerative disorders.

SUBMITTER: Kondo T

PROVIDER: S-EPMC2311353 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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Tlx3 exerts context-dependent transcriptional regulation and promotes neuronal differentiation from embryonic stem cells.

Kondo Takako T Sheets Patrick L PL Zopf David A DA Aloor Heather L HL Cummins Theodore R TR Chan Rebecca J RJ Hashino Eri E

Proceedings of the National Academy of Sciences of the United States of America 20080407 15

The T cell leukemia 3 (Tlx3) gene has been implicated in specification of glutamatergic sensory neurons in the spinal cord. In cranial sensory ganglia, Tlx3 is highly expressed in differentiating neurons during early embryogenesis. To study a role of Tlx3 during neural differentiation, mouse embryonic stem (ES) cells were transfected with a Tlx3 expression vector. ES cells stably expressing Tlx3 were grown in the presence or absence of a neural induction medium. In undifferentiated ES cells, the ...[more]

PMID: 18391221

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Project description:BackgroundUnderstanding the molecular mechanisms controlling pluripotency in embryonic stem cells (ESCs) is of central importance towards realizing their potentials in medicine and science. Cross-species examination of transcriptional co-expression allows elucidation of fundamental and species-specific mechanisms regulating ESC self-renewal or differentiation.Methodology/principal findingsWe examined transcriptional co-expression of ESCs from pathways to global networks under the framework of human-mouse comparisons. Using generalized singular value decomposition and comparative partition around medoids algorithms, evolutionarily conserved and divergent transcriptional co-expression regulating pluripotency were identified from ESC-critical pathways including ACTIVIN/NODAL, ATK/PTEN, BMP, CELL CYCLE, JAK/STAT, PI3K, TGFbeta and WNT. A set of transcription factors, including FOX, GATA, MYB, NANOG, OCT, PAX, SOX and STAT, and the FGF response element were identified that represent key regulators underlying the transcriptional co-expression. By transcriptional intervention conducted in silico, dynamic behavior of pathways was examined, which demonstrate how much and in which specific ways each gene or gene combination effects the behavior transition of a pathway in response to ESC differentiation or pluripotency induction. The global co-expression networks of ESCs were dominated by highly connected hub genes such as IGF2, JARID2, LCK, MYCN, NASP, OCT4, ORC1L, PHC1 and RUVBL1, which are possibly critical in determining the fate of ESCs.Conclusions/significanceThrough these studies, evolutionary conservation at genomic, transcriptomic, and network levels is shown to be an effective predictor of molecular factors and mechanisms controlling ESC development. Various hypotheses regarding mechanisms controlling ESC development were generated, which could be further validated by in vitro experiments. Our findings shed light on the systems-level understanding of how ESC differentiation or pluripotency arises from the connectivity or networks of genes, and provide a "road-map" for further experimental investigation.

Dataset Information

Tlx3 exerts context-dependent transcriptional regulation and promotes neuronal differentiation from embryonic stem cells.

Publications

Tlx3 exerts context-dependent transcriptional regulation and promotes neuronal differentiation from embryonic stem cells.

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