NPAS1 represses the generation of specific subtypes of cortical interneurons

Amelia Stanco; Ramón Pla; Daniel Vogt; Yiran Chen; Shyamali Mandal; Jamie Walker; Robert F Hunt; Susan Lindtner; Carolyn A Erdman; Andrew A Pieper; Steven P Hamilton; Duan Xu; Scott C Baraban; John L R Rubenstein

doi:10.1016/j.neuron.2014.10.040

NPAS1 represses the generation of specific subtypes of cortical interneurons

Neuron. 2014 Dec 3;84(5):940-53. doi: 10.1016/j.neuron.2014.10.040. Epub 2014 Nov 20.

Authors

Affiliations

¹ 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.
² Department of Psychiatry, Neuroscience Program, and the Nina Ireland Laboratory of Developmental Neurobiology, University of California, San Francisco, San Francisco, CA 94158-2324, USA.
³ Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94143, USA.
⁴ Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA.
⁵ Department of Neurological Surgery, Neuroscience Program, University of California, San Francisco, San Francisco, CA 94143, USA.
⁶ Department of Psychiatry and Neurology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
⁷ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Age Factors
Animals
Animals, Newborn
Autistic Disorder / genetics
Autistic Disorder / pathology
Basic Helix-Loop-Helix Transcription Factors / genetics
Basic Helix-Loop-Helix Transcription Factors / metabolism*
Cell Proliferation / genetics
Cells, Cultured
Cerebral Cortex / cytology*
Cerebral Cortex / embryology
Cerebral Cortex / growth & development
Embryo, Mammalian
Female
Gene Expression Regulation, Developmental / genetics
Gene Expression Regulation, Developmental / physiology*
Glutamate Decarboxylase / genetics
Glutamate Decarboxylase / metabolism
Humans
Interneurons / classification*
Interneurons / physiology*
LIM-Homeodomain Proteins / genetics
LIM-Homeodomain Proteins / metabolism
MAP Kinase Signaling System / genetics
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism*
Polymorphism, Single Nucleotide / genetics
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

Basic Helix-Loop-Helix Transcription Factors
LHX6 protein, mouse
LIM-Homeodomain Proteins
Nerve Tissue Proteins
Npas1 protein, mouse
Npas3 protein, mouse
Transcription Factors
Glutamate Decarboxylase
glutamate decarboxylase 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding