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

SummaryNeurofibromatosis-1 (NF-1) is a monogenic disorder caused by mutations in theNF1gene, which encodes the protein, Neurofibromin, an inhibitor of Ras GTPase activity. While NF-1 is often characterized by café-au-lait skin spots and benign tumors, the mechanisms underlying cognitive changes in NF-1 are poorly understood. Cortical GABAergic interneurons (CINs) are implicated in NF-1 pathology but cellular and molecular changes to CINs are poorly understood. We deletedNf1from the medial ganglionic eminence (MGE), which gives rise to both oligodendrocytes and CINs that express somatostatin and parvalbumin. Loss ofNf1led to a persistence of immature oligodendrocytes that prevented later born oligodendrocytes from occupying the cortex. Moreover, PV+ CINs were uniquely lost, without changes in SST+ CINs. We discovered that loss ofNf1results in a graded decrease inLhx6expression, the transcription factor necessary to establish SST+ and PV+ CINs, revealing a mechanism wherebyNf1regulates a critical CIN developmental milestone.