title: Lhx6 directly regulates Arx and CXCR7 to determine cortical interneuron fate and laminar position.
abstract: Cortical GABAergic interneurons have essential roles for information processing and their dysfunction is implicated in neuropsychiatric disorders. Transcriptional codes are elucidating mechanisms of interneuron specification in the MGE (a subcortical progenitor zone), which regulate their migration, integration, and function within cortical circuitry. Lhx6, a LIM-homeodomain transcription factor, is essential for specification of MGE-derived somatostatin and parvalbumin interneurons. Here, we demonstrate that some Lhx6⁻/⁻ MGE cells acquire a CGE-like fate. Using an in vivo MGE complementation/transplantation assay, we show that Lhx6-regulated genes Arx and CXCR7 rescue divergent aspects of Lhx6⁻/⁻ cell-fate and laminar mutant phenotypes and provide insight into a neonatal role for CXCR7 in MGE-derived interneuron lamination. Finally, Lhx6 directly binds in vivo to an Arx enhancer and to an intronic CXCR7 enhancer that remains active in mature interneurons. These data define the molecular identity of Lhx6 mutants and introduce technologies to test mechanisms in GABAergic interneuron differentiation.
authors.affiliation: Department of Psychiatry, Neuroscience Program and the Nina Ireland Laboratory of Developmental Neurobiology, University of California San Francisco, San Francisco, CA 94158, USA. Electronic address: daniel.vogt@ucsf.edu.
authors.forename: Daniel
authors.initials: D
authors.lastname: Vogt
authors.affiliation: Epilepsy Research Laboratory, Department of Neurological Surgery, 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, USA; Department of Cancer Biology and Pharmacology University of Illinois, Peoria, IL 61656, USA.
authors.forename: Shyamali
authors.initials: S
authors.lastname: Mandal
authors.affiliation: Department of Psychiatry, Neuroscience Program and the Nina Ireland Laboratory of Developmental Neurobiology, University of California San Francisco, San Francisco, CA 94158, USA.
authors.forename: Magnus
authors.initials: M
authors.lastname: Sandberg
authors.affiliation: Department of Psychiatry, Neuroscience Program and the Nina Ireland Laboratory of Developmental Neurobiology, University of California San Francisco, San Francisco, CA 94158, USA.
authors.forename: Shanni N
authors.initials: SN
authors.lastname: Silberberg
authors.affiliation: Department of Immunology and Hematology, Institute for Frontier Medical Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nagasawa
authors.affiliation: Institutes of Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: Zhengang
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Epilepsy Research Laboratory, Department of Neurological Surgery, 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, USA. Electronic address: john.rubenstein@ucsf.edu.
authors.forename: John L R
authors.initials: JL
authors.lastname: Rubenstein
mesh_terms: D000200:Action Potentials / Q000235:genetics; D000367:Age Factors; D000818:Animals; D002465:Cell Movement / Q000235:genetics*; D002540:Cerebral Cortex / Q000166:cytology*; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007395:Interneurons / Q000378:metabolism / Q000502:physiology*; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D054387:Receptors, CXCR / Q000235:genetics / Q000378:metabolism*; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C469265:ARX protein, mouse; D054360:Chemokine CXCL1; C501897:Cmkor1 protein, mouse; C475895:Cxcl1 protein, mouse; D018398:Homeodomain Proteins; C498504:LHX6 protein, mouse; D060850:LIM-Homeodomain Proteins; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D054387:Receptors, CXCR; D014157:Transcription Factors; C413663:fluorescent protein 583
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