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Genomic Resolution of DLX-Orchestrated Transcriptional Circuits Driving Development of Forebrain GABAergic Neurons

50 Pages Posted: 17 Apr 2019 Sneak Peek Status: Review Complete

See all articles by Susan Lindtner

Susan Lindtner

University of California, San Francisco (UCSF) - Nina Ireland Laboratory of Developmental Neurobiology

Rinaldo Catta-Preta

University of California, Davis - Department of Neurobiology, Physiology and Behavior; University of California, Davis - Department of Psychiatry and Behavioral Sciences

Hua Tian

University of California, San Francisco (UCSF) - Nina Ireland Laboratory of Developmental Neurobiology

Linda Su-Feher

University of California, Davis - Department of Neurobiology, Physiology and Behavior; University of California, Davis - Department of Psychiatry and Behavioral Sciences

James D. Price

University of California, San Francisco (UCSF) - Nina Ireland Laboratory of Developmental Neurobiology; University of California, San Francisco (UCSF) - Developmental and Stem Cell Biology PhD Program

Diane E. Dickel

University of California, Berkeley - Environmental Genomics and Systems Biology Division

Vanille Greiner

University of California, San Francisco (UCSF) - Department of Microbiology and Immunology

Shanni N. Silberberg

University of California, San Francisco (UCSF) - Nina Ireland Laboratory of Developmental Neurobiology

Gabriel L. McKinsey

University of California, San Francisco (UCSF) - Nina Ireland Laboratory of Developmental Neurobiology

Michael T. McManus

University of California, San Francisco (UCSF) - Department of Microbiology and Immunology

Len A. Pennacchio

University of California, Berkeley - Environmental Genomics and Systems Biology Division; Government of the United States of America - Joint Genome Institute; University of California, Berkeley - Comparative Biochemistry Program

Axel Visel

University of California, Berkeley - Environmental Genomics and Systems Biology Division; Government of the United States of America - Joint Genome Institute; University of California - School of Natural Sciences

Alexander Nord

University of California, Davis - Department of Neurobiology, Physiology and Behavior; University of California, Davis - Department of Psychiatry and Behavioral Sciences

John L.R. Rubenstein

University of California, San Francisco (UCSF) - Nina Ireland Laboratory of Developmental Neurobiology; University of California, San Francisco (UCSF) - Developmental and Stem Cell Biology PhD Program

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Abstract

DLX transcription factors (TFs) are master regulators of the developing vertebrate brain, driving forebrain GABAergic neuronal differentiation. Ablation of Dlx1&2 alters expression of genes that are critical for forebrain GABAergic development. We integrated epigenomic and transcriptomic analyses, complemented with in situ hybridization (ISH), and in vivo and in vitro studies of regulatory element (RE) function. This elucidated the DLX-organized gene regulatory network at genomic, cellular, and spatial level in mouse embryonic basal ganglia. DLX TFs perform dual activating and repressing functions; the consequences of their binding were determined by the sequence and genomic context of target loci. Our results reveal and, in part, explain the paradox of widespread DLX binding contrasted with a limited subset of target loci that are sensitive at the epigenomic and transcriptomic level to Dlx1&2 ablation. The regulatory properties identified here for DLX TFs suggest general mechanisms by which TFs orchestrate dynamic expression programs underlying neurodevelopment.

Suggested Citation

Lindtner, Susan and Catta-Preta, Rinaldo and Tian, Hua and Su-Feher, Linda and Price, James D. and Dickel, Diane E. and Greiner, Vanille and Silberberg, Shanni N. and McKinsey, Gabriel L. and McManus, Michael T. and Pennacchio, Len A. and Visel, Axel and Nord, Alexander and Rubenstein, John L.R., Genomic Resolution of DLX-Orchestrated Transcriptional Circuits Driving Development of Forebrain GABAergic Neurons (April 16, 2019). Available at SSRN: https://ssrn.com/abstract=3372973 or http://dx.doi.org/10.2139/ssrn.3372973
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Susan Lindtner

University of California, San Francisco (UCSF) - Nina Ireland Laboratory of Developmental Neurobiology

United States

Rinaldo Catta-Preta

University of California, Davis - Department of Neurobiology, Physiology and Behavior

United States

University of California, Davis - Department of Psychiatry and Behavioral Sciences

One Shields Avenue
Davis, CA 95616
United States

Hua Tian

University of California, San Francisco (UCSF) - Nina Ireland Laboratory of Developmental Neurobiology

United States

Linda Su-Feher

University of California, Davis - Department of Neurobiology, Physiology and Behavior

United States

University of California, Davis - Department of Psychiatry and Behavioral Sciences

One Shields Avenue
Davis, CA 95616
United States

James D. Price

University of California, San Francisco (UCSF) - Nina Ireland Laboratory of Developmental Neurobiology

United States

University of California, San Francisco (UCSF) - Developmental and Stem Cell Biology PhD Program

Third Avenue and Parnassus
San Francisco, CA 94143
United States

Diane E. Dickel

University of California, Berkeley - Environmental Genomics and Systems Biology Division

United States

Vanille Greiner

University of California, San Francisco (UCSF) - Department of Microbiology and Immunology

San Francisco, CA 94143
United States

Shanni N. Silberberg

University of California, San Francisco (UCSF) - Nina Ireland Laboratory of Developmental Neurobiology

United States

Gabriel L. McKinsey

University of California, San Francisco (UCSF) - Nina Ireland Laboratory of Developmental Neurobiology

United States

Michael T. McManus

University of California, San Francisco (UCSF) - Department of Microbiology and Immunology

Third Avenue and Parnassus
San Francisco, CA 94143
United States

Len A. Pennacchio

University of California, Berkeley - Environmental Genomics and Systems Biology Division

United States

Government of the United States of America - Joint Genome Institute

United States

University of California, Berkeley - Comparative Biochemistry Program

United States

Axel Visel

University of California, Berkeley - Environmental Genomics and Systems Biology Division

United States

Government of the United States of America - Joint Genome Institute

United States

University of California - School of Natural Sciences

United States

Alexander Nord (Contact Author)

University of California, Davis - Department of Neurobiology, Physiology and Behavior ( email )

United States

University of California, Davis - Department of Psychiatry and Behavioral Sciences ( email )

One Shields Avenue
Davis, CA 95616
United States

John L.R. Rubenstein

University of California, San Francisco (UCSF) - Nina Ireland Laboratory of Developmental Neurobiology ( email )

United States

University of California, San Francisco (UCSF) - Developmental and Stem Cell Biology PhD Program ( email )

Third Avenue and Parnassus
San Francisco, CA 94143
United States

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