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

Abstract

Neurofibromatosis 1 (NF1) is caused by mutations in the <i>NF1</i> 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 <i>Nf1</i> from the medial ganglionic eminence, which gives rise to both oligodendrocytes and CINs that express somatostatin and parvalbumin. <i>Nf1</i> 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 <i>Nf1</i>, without changes in somatostatin (SST)-positive CINs. We discovered that loss of <i>Nf1</i> results in a dose-dependent decrease in <i>Lhx6</i> 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.