Nf1 deletion results in depletion of the Lhx6 transcription factor and a specific loss of parvalbumin+ cortical interneurons
2019
Neurofibromatosis-1 (NF-1) is a
monogenicdisorder caused by mutations in the NF1 gene, which encodes the protein, Neurofibromin, an inhibitor of Ras GTPase activity. While NF-1 is often characterized by cafe-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 deleted Nf1 from the medial
ganglionic eminence(MGE), which gives rise to both
oligodendrocytesand CINs that express somatostatin and
parvalbumin. Loss of Nf1 led to a persistence of immature
oligodendrocytesthat prevented later born
oligodendrocytesfrom occupying the cortex. Moreover, PV+ CINs were uniquely lost, without changes in SST+ CINs. We discovered that loss of Nf1 results in a graded decrease in Lhx6 expression, the transcription factor necessary to establish SST+ and PV+ CINs, revealing a mechanism whereby Nf1 regulates a critical CIN developmental milestone.
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