title: Transcription factor Lhx2 is necessary and sufficient to suppress astrogliogenesis and promote neurogenesis in the developing hippocampus.
abstract: The sequential production of neurons and astrocytes from neuroepithelial precursors is a fundamental feature of central nervous system development. We report that LIM-homeodomain (LIM-HD) transcription factor Lhx2 regulates this transition in the developing hippocampus. Disrupting Lhx2 function in the embryonic hippocampus by in utero electroporation and in organotypic slice culture caused the premature production of astrocytes at stages when neurons are normally generated. Lhx2 function is therefore necessary to suppress astrogliogenesis during the neurogenic period. Furthermore, Lhx2 overexpression was sufficient to suppress astrogliogenesis and prolong the neurogenic period. We provide evidence that Lhx2 overexpression can counteract the instructive astrogliogenic effect of Notch activation. Lhx2 overexpression was also able to override and suppress the activation of the GFAP promoter by Nfia, a Notch-regulated transcription factor that is required for gliogenesis. Thus, Lhx2 appears to act as a "brake" on Notch/Nfia-mediated astrogliogenesis. This critical role for Lhx2 is spatially restricted to the hippocampus, because loss of Lhx2 function in the neocortex did not result in premature astrogliogenesis at the expense of neurogenesis. Our results therefore place Lhx2 as a central regulator of the neuron-glia cell fate decision in the hippocampus and reveal a striking regional specificity of this fundamental function within the dorsal telencephalon.
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Subramanian
authors.forename: Anindita
authors.initials: A
authors.lastname: Sarkar
authors.forename: Ashwin S
authors.initials: AS
authors.lastname: Shetty
authors.forename: Bhavana
authors.initials: B
authors.lastname: Muralidharan
authors.forename: Hari
authors.initials: H
authors.lastname: Padmanabhan
authors.forename: Michael
authors.initials: M
authors.lastname: Piper
authors.forename: Edwin S
authors.initials: ES
authors.lastname: Monuki
authors.forename: Ingolf
authors.initials: I
authors.lastname: Bach
authors.forename: Richard M
authors.initials: RM
authors.lastname: Gronostajski
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Richards
authors.forename: Shubha
authors.initials: S
authors.lastname: Tole
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000502:physiology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000196:embryology* / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D060850:LIM-Homeodomain Proteins; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051839:NFI Transcription Factors / Q000502:physiology; D019579:Neocortex / Q000166:cytology / Q000196:embryology / Q000502:physiology; D058953:Neural Stem Cells / Q000166:cytology / Q000502:physiology; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D011247:Pregnancy; D051880:Receptors, Notch / Q000502:physiology; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; C489784:Lhx2 protein, mouse; D051839:NFI Transcription Factors; C497646:Nfia protein, mouse; D051880:Receptors, Notch; D014157:Transcription Factors