title: 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.
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.
authors.affiliation: Laboratory of Developmental Genetics, Université Libre de Bruxelles (ULB), Institute of Molecular Biology and Medicine, and ULB Neuroscience Institute, B-6041 Gosselies, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Hanotel
authors.affiliation: Laboratory of Developmental Genetics, Université Libre de Bruxelles (ULB), Institute of Molecular Biology and Medicine, and ULB Neuroscience Institute, B-6041 Gosselies, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bessodes
authors.affiliation: Laboratory of Developmental Genetics, Université Libre de Bruxelles (ULB), Institute of Molecular Biology and Medicine, and ULB Neuroscience Institute, B-6041 Gosselies, Belgium.
authors.forename: Aurore
authors.initials: A
authors.lastname: Thélie
authors.affiliation: Department of Developmental Biochemistry, Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), University of Goettingen, 37077 Goettingen, Germany.
authors.forename: Marie
authors.initials: M
authors.lastname: Hedderich
authors.affiliation: UPR CNRS 3294 Neurobiology and Development, Université Paris Sud, 91405 Orsay Cedex, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Parain
authors.affiliation: Laboratory of Molecular Virology, Université Libre de Bruxelles (ULB), Institute of Molecular Biology and Medicine, B-6041 Gosselies, Belgium.
authors.forename: Benoit
authors.initials: B
authors.lastname: Van Driessche
authors.affiliation: Laboratory of Developmental Genetics, Université Libre de Bruxelles (ULB), Institute of Molecular Biology and Medicine, and ULB Neuroscience Institute, B-6041 Gosselies, Belgium.
authors.forename: Karina De Oliveira
authors.initials: Kde O
authors.lastname: Brandão
authors.affiliation: Laboratory of Developmental Genetics, Université Libre de Bruxelles (ULB), Institute of Molecular Biology and Medicine, and ULB Neuroscience Institute, B-6041 Gosselies, Belgium.
authors.forename: Sadia
authors.initials: S
authors.lastname: Kricha
authors.affiliation: DanStem, University of Copenhagen, 3B Blegdamsvej, DK-2200 Copenhagen N, Denmark.
authors.forename: Mette C
authors.initials: MC
authors.lastname: Jorgensen
authors.affiliation: DanStem, University of Copenhagen, 3B Blegdamsvej, DK-2200 Copenhagen N, Denmark.
authors.forename: Anne
authors.initials: A
authors.lastname: Grapin-Botton
authors.affiliation: DanStem, University of Copenhagen, 3B Blegdamsvej, DK-2200 Copenhagen N, Denmark.
authors.forename: Palle
authors.initials: P
authors.lastname: Serup
authors.affiliation: Laboratory of Molecular Virology, Université Libre de Bruxelles (ULB), Institute of Molecular Biology and Medicine, B-6041 Gosselies, Belgium.
authors.forename: Carine
authors.initials: C
authors.lastname: Van Lint
authors.affiliation: UPR CNRS 3294 Neurobiology and Development, Université Paris Sud, 91405 Orsay Cedex, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Perron
authors.affiliation: Department of Developmental Biochemistry, Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), University of Goettingen, 37077 Goettingen, Germany.
authors.forename: Tomas
authors.initials: T
authors.lastname: Pieler
authors.affiliation: Department of Developmental Biochemistry, Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), University of Goettingen, 37077 Goettingen, Germany.
authors.forename: Kristine A
authors.initials: KA
authors.lastname: Henningfeld
authors.affiliation: Laboratory of Developmental Genetics, Université Libre de Bruxelles (ULB), Institute of Molecular Biology and Medicine, and ULB Neuroscience Institute, B-6041 Gosselies, Belgium. Electronic address: ebellefr@ulb.ac.be.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Bellefroid
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002642:Chick Embryo; D017931:DNA Primers / Q000235:genetics; D018274:Electroporation; D059330:GABAergic Neurons / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D051379:Mice; D054259:Neural Tube / Q000166:cytology / Q000196:embryology*; D051762:PAX2 Transcription Factor / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D017931:DNA Primers; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D051762:PAX2 Transcription Factor; D029867:Xenopus Proteins; C581699:Ptf1a protein, Xenopus; C587306:Prdm13 protein, Xenopus
keywords: GABAergic neuron; Glutamatergic neuron; Histone methyltransferase; Neurog2; Pax2; Prdm genes; Ptf1a; Retina; Spinal cord; Tlx3