Abstract
Multiple excitatory and inhibitory interneurons form the motor circuit with motor neurons in the ventral spinal cord. Notch signaling initiates the diversification of immature V2-interneurons into excitatory V2a-interneurons and inhibitory V2b-interneurons. Here, we provide a transcriptional regulatory mechanism underlying their balanced production. LIM-only protein LMO4 controls this binary cell fate choice by regulating the activity of V2a- and V2b-specific LIM complexes inversely. In the spinal cord, LMO4 induces GABAergic V2b-interneurons in collaboration with SCL and inhibits Lhx3 from generating glutamatergic V2a-interneuons. In LMO4;SCL compound mutant embryos, V2a-interneurons increase markedly at the expense of V2b-interneurons. We further demonstrate that LMO4 nucleates the assembly of a novel LIM-complex containing SCL, Gata2, and NLI. This complex activates specific enhancers in V2b-genes consisting of binding sites for SCL and Gata2, thereby promoting V2b-interneuron fate. Thus, LMO4 plays essential roles in directing a balanced generation of inhibitory and excitatory neurons in the ventral spinal cord.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Cell Adhesion Molecules, Neuronal
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Cell Differentiation / drug effects
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Cells, Cultured
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Chickens
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Chromatin Immunoprecipitation / methods
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Embryo, Mammalian
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GATA3 Transcription Factor / genetics
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GATA3 Transcription Factor / metabolism
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Gene Expression Regulation, Developmental / genetics
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Gene Expression Regulation, Developmental / physiology*
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Homeodomain Proteins / physiology*
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Humans
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Interneurons / physiology*
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LIM Domain Proteins
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Mice
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Mice, Mutant Strains
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Models, Biological
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Multiprotein Complexes / genetics
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Multiprotein Complexes / metabolism
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Neural Cell Adhesion Molecules / genetics
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Neural Cell Adhesion Molecules / metabolism
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Neural Inhibition / physiology*
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Protein Binding / genetics
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Proto-Oncogene Proteins / genetics
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RNA, Messenger / metabolism
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Spinal Cord / cytology
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T-Cell Acute Lymphocytic Leukemia Protein 1
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription Factors / physiology*
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Transfection / methods
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Vesicular Glutamate Transport Protein 2 / genetics
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gamma-Aminobutyric Acid / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Basic Helix-Loop-Helix Transcription Factors
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Cell Adhesion Molecules, Neuronal
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DNA-Binding Proteins
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GATA3 Transcription Factor
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Gata3 protein, mouse
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Homeodomain Proteins
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LIM Domain Proteins
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Lmo4 protein, mouse
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Multiprotein Complexes
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Neural Cell Adhesion Molecules
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Proto-Oncogene Proteins
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RNA, Messenger
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Slc17a6 protein, mouse
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Ssbp3 protein, mouse
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T-Cell Acute Lymphocytic Leukemia Protein 1
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Tal1 protein, mouse
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Transcription Factors
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Vesicular Glutamate Transport Protein 2
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Vsx2 protein, mouse
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neuroligin 1
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gamma-Aminobutyric Acid