Nf1deletion results in depletion of theLhx6transcription factor and a specific loss of parvalbumin+cortical interneurons

Abstract

Neurofibromatosis 1 (NF1) is caused by mutations in theNF1gene, 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 mouseNf1from the medial ganglionic eminence, which gives rise to both oligodendrocytes and CINs that express somatostatin and parvalbumin.Nf1loss 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 ofNf1, without changes in somatostatin (SST)-positive CINs. We discovered that loss ofNf1results in a dose-dependent decrease inLhx6expression, 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.