Journal Article

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

Pai, Emily Ling-Lin, Bilinovich, Stephanie M., Angara, Kartik, Nguyen, Julie T., Li, Katie X., Stafford, April M., Rubenstein, John L., Vogt, Daniel, Paul, Anirban

2020

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Aminoacetonitrile - administration & dosage / Aminoacetonitrile - analogs & derivatives / Animals / Biological Sciences / Cells, Cultured / Cerebral cortex / Cerebral Cortex - cytology / Cerebral Cortex - pathology / Clonal deletion / Depletion / Disease Models, Animal / Embryo, Mammalian / Female / GABAergic Neurons - metabolism / GABAergic Neurons - pathology / Humans / Inhibitors / Interneurons / Interneurons - metabolism / Interneurons - pathology / LIM-Homeodomain Proteins - metabolism / MAP Kinase Signaling System - drug effects / Median Eminence - cytology / MEK inhibitors / Mice / Mice, Knockout / Mutation / Nerve Tissue Proteins - metabolism / Neurofibromatosis / Neurofibromatosis 1 - genetics / Neurofibromatosis 1 - pathology / Neurofibromin 1 / Neurofibromin 1 - genetics / Neurofibromin 1 - metabolism / Neuroglia - cytology / Neuroscience / Oligodendrocytes / Parvalbumin / Parvalbumins - metabolism / Primary Cell Culture / ras GTPase-Activating Proteins - metabolism / Ras protein / Recklinghausen's disease / Somatostatin / Somatostatin - metabolism / Transcription factors / Transcription Factors - metabolism / γ-Aminobutyric acid