The Prdm13 histone methyltransferase encoding gene is a Ptf1a-Rbpj downstream target that suppresses glutamatergic and promotes GABAergic neuronal fate in the dorsal neural tube

Dev Biol. 2014 Feb 15;386(2):340-57. doi: 10.1016/j.ydbio.2013.12.024. Epub 2013 Dec 24.

Abstract

The basic helix-loop-helix (bHLH) transcriptional activator Ptf1a determines inhibitory GABAergic over excitatory glutamatergic neuronal cell fate in progenitors of the vertebrate dorsal spinal cord, cerebellum and retina. In an in situ hybridization expression survey of PR domain containing genes encoding putative chromatin-remodeling zinc finger transcription factors in Xenopus embryos, we identified Prdm13 as a histone methyltransferase belonging to the Ptf1a synexpression group. Gain and loss of Ptf1a function analyses in both frog and mice indicates that Prdm13 is positively regulated by Ptf1a and likely constitutes a direct transcriptional target. We also showed that this regulation requires the formation of the Ptf1a-Rbp-j complex. Prdm13 knockdown in Xenopus embryos and in Ptf1a overexpressing ectodermal explants lead to an upregulation of Tlx3/Hox11L2, which specifies a glutamatergic lineage and a reduction of the GABAergic neuronal marker Pax2. It also leads to an upregulation of Prdm13 transcription, suggesting an autonegative regulation. Conversely, in animal caps, Prdm13 blocks the ability of the bHLH factor Neurog2 to activate Tlx3. Additional gain of function experiments in the chick neural tube confirm that Prdm13 suppresses Tlx3(+)/glutamatergic and induces Pax2(+)/GABAergic neuronal fate. Thus, Prdm13 is a novel crucial component of the Ptf1a regulatory pathway that, by modulating the transcriptional activity of bHLH factors such as Neurog2, controls the balance between GABAergic and glutamatergic neuronal fate in the dorsal and caudal part of the vertebrate neural tube.

Keywords: GABAergic neuron; Glutamatergic neuron; Histone methyltransferase; Neurog2; Pax2; Prdm genes; Ptf1a; Retina; Spinal cord; Tlx3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Differentiation / physiology*
  • Chick Embryo
  • DNA Primers / genetics
  • Electroporation
  • GABAergic Neurons / physiology*
  • Gene Expression Regulation, Developmental / physiology*
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Immunohistochemistry
  • Immunoprecipitation
  • In Situ Hybridization
  • Mice
  • Neural Tube / cytology
  • Neural Tube / embryology*
  • PAX2 Transcription Factor / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Xenopus Proteins / genetics
  • Xenopus Proteins / metabolism*
  • Xenopus laevis

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • DNA Primers
  • PAX2 Transcription Factor
  • Ptf1a protein, Xenopus
  • Xenopus Proteins
  • Histone Methyltransferases
  • Prdm13 protein, Xenopus
  • Histone-Lysine N-Methyltransferase