title: NPAS1 represses the generation of specific subtypes of cortical interneurons.
abstract: Little is known about genetic mechanisms that regulate the ratio of cortical excitatory and inhibitory neurons. We show that NPAS1 and NPAS3 transcription factors (TFs) are expressed in progenitor domains of the mouse basal ganglia (subpallium, MGE, and CGE). NPAS1(-/-) mutants had increased proliferation, ERK signaling, and expression of Arx in the MGE and CGE. NPAS1(-/-) mutants also had increased neocortical inhibition (sIPSC and mIPSC) and generated an excess of somatostatin(+) (SST) (MGE-derived) and vasoactive intestinal polypeptide(+) (VIP) (CGE-derived) neocortical interneurons, but had a normal density of parvalbumin(+) (PV) (MGE-derived) interneurons. In contrast, NPAS3(-/-) mutants showed decreased proliferation and ERK signaling in progenitors of the ganglionic eminences and had fewer SST(+) and VIP(+) interneurons. NPAS1 repressed activity of an Arx enhancer, and Arx overexpression resulted in increased proliferation of CGE progenitors. These results provide insights into genetic regulation of cortical interneuron numbers and cortical inhibitory tone.
authors.affiliation: Department of Psychiatry, Neuroscience Program, and the Nina Ireland Laboratory of Developmental Neurobiology, University of California, San Francisco, San Francisco, CA 94158-2324, USA. Electronic address: amelia.stanco@ucsf.edu.
authors.forename: Amelia
authors.initials: A
authors.lastname: Stanco
authors.affiliation: Department of Psychiatry, Neuroscience Program, and the Nina Ireland Laboratory of Developmental Neurobiology, University of California, San Francisco, San Francisco, CA 94158-2324, USA.
authors.forename: Ramón
authors.initials: R
authors.lastname: Pla
authors.affiliation: Department of Psychiatry, Neuroscience Program, and the Nina Ireland Laboratory of Developmental Neurobiology, University of California, San Francisco, San Francisco, CA 94158-2324, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Vogt
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Yiran
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Psychiatry, Neuroscience Program, and the Nina Ireland Laboratory of Developmental Neurobiology, University of California, San Francisco, San Francisco, CA 94158-2324, USA.
authors.forename: Shyamali
authors.initials: S
authors.lastname: Mandal
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Walker
authors.affiliation: Department of Neurological Surgery, Neuroscience Program, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Hunt
authors.affiliation: Department of Psychiatry, Neuroscience Program, and the Nina Ireland Laboratory of Developmental Neurobiology, University of California, San Francisco, San Francisco, CA 94158-2324, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Lindtner
authors.affiliation: Department of Psychiatry, Neuroscience Program, and the Nina Ireland Laboratory of Developmental Neurobiology, University of California, San Francisco, San Francisco, CA 94158-2324, USA.
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Erdman
authors.affiliation: Department of Psychiatry and Neurology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Pieper
authors.affiliation: Department of Psychiatry, Neuroscience Program, and the Nina Ireland Laboratory of Developmental Neurobiology, University of California, San Francisco, San Francisco, CA 94158-2324, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Hamilton
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Duan
authors.initials: D
authors.lastname: Xu
authors.affiliation: Department of Neurological Surgery, Neuroscience Program, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Baraban
authors.affiliation: Department of Psychiatry, Neuroscience Program, and the Nina Ireland Laboratory of Developmental Neurobiology, University of California, San Francisco, San Francisco, CA 94158-2324, USA. Electronic address: john.rubenstein@ucsf.edu.
authors.forename: John L R
authors.initials: JL
authors.lastname: Rubenstein
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001321:Autistic Disorder / Q000235:genetics / Q000473:pathology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000196:embryology / Q000254:growth & development; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007395:Interneurons / Q000145:classification* / Q000502:physiology*; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005968:Glutamate Decarboxylase; D060850:LIM-Homeodomain Proteins; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; C498504:LHX6 protein, mouse; C512770:Npas1 protein, mouse; C492587:Npas3 protein, mouse; C402565:glutamate decarboxylase 1