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Proc Natl Acad Sci U S A. 2020 Mar 17;117(11):6189-6195. doi: 10.1073/pnas.1915458117. Epub 2020 Mar 2.

Nf1 deletion results in depletion of the Lhx6 transcription factor and a specific loss of parvalbumin+ cortical interneurons.

Author information

1
Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, MI 49503.
2
Department of Psychiatry, University of California, San Francisco, CA 94158.
3
Neuroscience Program, University of California, San Francisco, CA 94158.
4
Nina Ireland Laboratory of Developmental Neurobiology, University of California, San Francisco, CA 94158.
5
Department of Neural and Behavioral Sciences, PennState University, Hershey, PA 17033.
6
Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, MI 49503; vogtdan2@msu.edu.
7
Neuroscience Program, Michigan State University, Grand Rapids, MI 49503.

Abstract

Neurofibromatosis 1 (NF1) is caused by mutations in the NF1 gene, which encodes the protein, neurofibromin, an inhibitor of Ras activity. Cortical GABAergic interneurons (CINs) are implicated in NF1 pathology, but the cellular and molecular changes to CINs are unknown. We deleted mouse Nf1 from the medial ganglionic eminence, which gives rise to both oligodendrocytes and CINs that express somatostatin and parvalbumin. Nf1 loss led to a persistence of immature oligodendrocytes that prevented later-generated oligodendrocytes from occupying the cortex. Moreover, molecular and cellular properties of parvalbumin (PV)-positive CINs were altered by the loss of Nf1, without changes in somatostatin (SST)-positive CINs. We discovered that loss of Nf1 results in a dose-dependent decrease in Lhx6 expression, the transcription factor necessary to establish SST+ and PV+ CINs, which was rescued by the MEK inhibitor SL327, revealing a mechanism whereby a neurofibromin/Ras/MEK pathway regulates a critical CIN developmental milestone.

KEYWORDS:

MGE; cortical interneuron; oligodendrocyte

PMID:
32123116
PMCID:
PMC7084085
[Available on 2020-09-02]
DOI:
10.1073/pnas.1915458117

Conflict of interest statement

The authors declare no competing interest.

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