title: Gene co-regulation by Fezf2 selects neurotransmitter identity and connectivity of corticospinal neurons.
abstract: The neocortex contains an unparalleled diversity of neuronal subtypes, each defined by distinct traits that are developmentally acquired under the control of subtype-specific and pan-neuronal genes. The regulatory logic that orchestrates the expression of these unique combinations of genes is unknown for any class of cortical neuron. Here, we report that Fezf2 is a selector gene able to regulate the expression of gene sets that collectively define mouse corticospinal motor neurons (CSMN). We find that Fezf2 directly induces the glutamatergic identity of CSMN via activation of Vglut1 (Slc17a7) and inhibits a GABAergic fate by repressing transcription of Gad1. In addition, we identify the axon guidance receptor EphB1 as a target of Fezf2 necessary to execute the ipsilateral extension of the corticospinal tract. Our data indicate that co-regulated expression of neuron subtype-specific and pan-neuronal gene batteries by a single transcription factor is one component of the regulatory logic responsible for the establishment of CSMN identity.
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Simona
authors.initials: S
authors.lastname: Lodato
authors.affiliation: 1] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. [2] Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Molyneaux
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Zuccaro
authors.affiliation: 1] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3] Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Loyal A
authors.initials: LA
authors.lastname: Goff
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Hsu-Hsin
authors.initials: HH
authors.lastname: Chen
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Yuan
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Meleski
authors.affiliation: Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Emi
authors.initials: E
authors.lastname: Takahashi
authors.affiliation: 1] Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. [2] Department of Biochemistry and Molecular Biology, Center for Eukaryotic Gene Regulation, The Pennsylvania State University, University Park, Pennsylvania, USA.
authors.forename: Shaun
authors.identifier: 0000000226411807
authors.initials: S
authors.lastname: Mahony
authors.affiliation: 1] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3] Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Rinn
authors.affiliation: 1] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. [2] Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: David K
authors.initials: DK
authors.lastname: Gifford
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Paola
authors.initials: P
authors.lastname: Arlotta
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D016153:Genes, Suppressor; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000145:classification / Q000378:metabolism* / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011712:Pyramidal Tracts / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; C412364:Zfp312 protein, mouse