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J Neurosci. 2017 Nov 15;37(46):11245-11254. doi: 10.1523/JNEUROSCI.1535-17.2017. Epub 2017 Oct 12.

Dmrt5, a Novel Neurogenic Factor, Reciprocally Regulates Lhx2 to Control the Neuron-Glia Cell-Fate Switch in the Developing Hippocampus.

Author information

1
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400 005, India.
2
Université Libre de Bruxelles (ULB), ULB Institute of Neuroscience, B-6041 Gosselies, Belgium.
3
Centre of Excellence in Epigenetics, Indian Institute of Science, Education and Research, Pune 411 008, India, and.
4
Department of Life Sciences, Sophia College for Women, Mumbai 400 026, India.
5
Université Libre de Bruxelles (ULB), ULB Institute of Neuroscience, B-6041 Gosselies, Belgium, ebellefr@ulb.ac.be shubhatole@gmail.com.
6
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400 005, India, ebellefr@ulb.ac.be shubhatole@gmail.com.

Abstract

Regulation of the neuron-glia cell-fate switch is a critical step in the development of the CNS. Previously, we demonstrated that Lhx2 is a necessary and sufficient regulator of this process in the mouse hippocampal primordium, such that Lhx2 overexpression promotes neurogenesis and suppresses gliogenesis, whereas loss of Lhx2 has the opposite effect. We tested a series of transcription factors for their ability to mimic Lhx2 overexpression and suppress baseline gliogenesis, and also to compensate for loss of Lhx2 and suppress the resulting enhanced level of gliogenesis in the hippocampus. Here, we demonstrate a novel function of Dmrt5/Dmrta2 as a neurogenic factor in the developing hippocampus. We show that Dmrt5, as well as known neurogenic factors Neurog2 and Pax6, can each not only mimic Lhx2 overexpression, but also can compensate for loss of Lhx2 to different extents. We further uncover a reciprocal regulatory relationship between Dmrt5 and Lhx2, such that each can compensate for loss of the other. Dmrt5 and Lhx2 also have opposing regulatory control on Pax6 and Neurog2, indicating a complex bidirectionally regulated network that controls the neuron-glia cell-fate switch.SIGNIFICANCE STATEMENT We identify Dmrt5 as a novel regulator of the neuron-glia cell-fate switch in the developing hippocampus. We demonstrate Dmrt5 to be neurogenic, and reciprocally regulated by Lhx2: loss of either factor promotes gliogenesis; overexpression of either factor suppresses gliogenesis and promotes neurogenesis; each can substitute for loss of the other. Furthermore, each factor has opposing effects on established neurogenic genes Neurog2 and Pax6 Dmrt5 is known to suppress their expression, and we show that Lhx2 is required to maintain it. Our study reveals a complex regulatory network with bidirectional control of a fundamental feature of CNS development, the control of the production of neurons versus astroglia in the developing hippocampus.Finally, we confirm that Lhx2 binds a highly conserved putative enhancer of Dmrt5, suggesting an evolutionarily conserved regulatory relationship between these factors. Our findings uncover a complex network that involves Lhx2, Dmrt5, Neurog2, and Pax6, and that ensures the appropriate amount and timing of neurogenesis and gliogenesis in the developing hippocampus.

KEYWORDS:

cell fate; glia; hippocampus; neuron

PMID:
29025924
PMCID:
PMC5688529
DOI:
10.1523/JNEUROSCI.1535-17.2017
[Indexed for MEDLINE]
Free PMC Article

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