Tlx3 promotes glutamatergic neuronal subtype specification through direct interactions with the chromatin modifier CBP

Atsushi Shimomura, Dharmeshkumar Patel, Sarah M. Wilson, Karl R. Koehler, Rajesh Khanna, Eri Hashino

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Nervous system development relies on the generation of precise numbers of excitatory and inhibitory neurons. The homeodomain transcription factor, T-cell leukemia 3 (Tlx3), functions as the master neuronal fate regulator by instructively promoting the specification of glutamatergic excitatory neurons and suppressing the specification of gamma-aminobutyric acid (GABAergic) neurons. However, how Tlx3 promotes glutamatergic neuronal subtype specification is poorly understood. In this study, we found that Tlx3 directly interacts with the epigenetic co-activator cyclic adenosine monophosphate (cAMP)-response element-binding protein (CREB)-binding protein (CBP) and that the Tlx3 homeodomain is essential for this interaction. The interaction between Tlx3 and CBP was enhanced by the three amino acid loop extension (TALE)-class homeodomain transcription factor, pre-B-cell leukemia transcription factor 3 (Pbx3). Using mouse embryonic stem (ES) cells stably expressing Tlx3, we found that the interaction between Tlx3 and CBP became detectable only after these Tlx3-expressing ES cells were committed to a neural lineage, which coincided with increased Pbx3 expression during neural differentiation from ES cells. Forced expression of mutated Tlx3 lacking the homeodomain in ES cells undergoing neural differentiation resulted in significantly reduced expression of glutamatergic neuronal subtype markers, but had little effect on the expression on pan neural markers. Collectively, our results strongly suggest that functional interplay between Tlx3 and CBP plays a critical role in neuronal subtype specification, providing novel insights into the epigenetic regulatory mechanism that modulates the transcriptional efficacy of a selective set of neuronal subtype-specific genes during differentiation.

Original languageEnglish (US)
Article numbere0135060
JournalPLoS One
Volume10
Issue number8
DOIs
StatePublished - Aug 10 2015

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CREB-Binding Protein
modifiers (genes)
Embryonic Stem Cells
Stem cells
Chromatin
embryonic stem cells
chromatin
binding proteins
Neurons
Specifications
Epigenomics
Carrier Proteins
Transcription Factors
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
Transcription Factor 3
transcription factors
neurons
T-Cell Leukemia
GABAergic Neurons
leukemia

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Tlx3 promotes glutamatergic neuronal subtype specification through direct interactions with the chromatin modifier CBP. / Shimomura, Atsushi; Patel, Dharmeshkumar; Wilson, Sarah M.; Koehler, Karl R.; Khanna, Rajesh; Hashino, Eri.

In: PLoS One, Vol. 10, No. 8, e0135060, 10.08.2015.

Research output: Contribution to journalArticle

Shimomura, Atsushi ; Patel, Dharmeshkumar ; Wilson, Sarah M. ; Koehler, Karl R. ; Khanna, Rajesh ; Hashino, Eri. / Tlx3 promotes glutamatergic neuronal subtype specification through direct interactions with the chromatin modifier CBP. In: PLoS One. 2015 ; Vol. 10, No. 8.
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