UBC Theses and Dissertations
Role of Nf1 signaling in regulating pigmentation in the mouse Deo, Mugdha Anand
Neurofibromatosis type 1 is caused by mutations in neurofibromin (NF1). Neurofibromas, which are Schwann cell based tumors, and skin hyper-pigmentation are characteristic of NF1 loss. Melanocytes differentiate from Schwann cell precursors (SCPs) during development, suggesting that there may be a mechanistic link between these NF1-related manifestations. In this thesis, we use Cre-LoxP technology to test the cell types that require Nf1 for normal pigmentation. We discovered that an Nf1 targeted knockout (Nf1tm1Par) and an ENU-generated N1453K substitution in Nf1 (Nf1Dsk9) are associated with darker skin in mice. Nf1Dsk9/Nf1Dsk9 embryos exhibit increased numbers of melanoblasts at E10.5, and Nf1 -/- knock out in already committed melanoblasts causes dermal and epidermal hyper-pigmentation. In contrast, Nf1Dsk9/+ embryos exhibit an increase in the number of melanoblasts beginning at E12.5, and Nf1 +/- knockout in already committed melanoblasts has no effect on skin pigmentation. Nf1 haploinsufficiency in SCPs causes hyper-pigmentation of the dermis (but not the epidermis) in tamoxifen-inducible Plp1-CreER/+; Nf1tm1Par/+ mice when tamoxifen is administered at E11.5. Consistent with a lack of epidermal darkening in these mice, we found that cells expressing Plp1-CreER at E11.5 do not persist in the adult epidermis. We found that Nf1 regulates skin pigmentation by an endothelin-dependent, as well as an independent mechanism. Nf1Dsk9/+;Ednrbs-l/Ednrbs-l mice lack tail skin pigmentation, like +/+;Ednrbs-l/Ednrbs-l mice. However, Nf1Dsk9/+;Ednrbs-l/Ednrbs-l mice exhibit an increased percentage of pigmented coat compared to +/+;Ednrbs-l/Ednrbs-l mice. Our data suggests that there are at least two mechanisms by which Nf1 regulates pigmentation in mice. Two copies of Nf1 are required to determine the appropriate number of melanoblasts that differentiate from bipotent melanoctye-SCPs. Subsequently, at least one copy of Nf1 is required to restrain the number of melanoblasts in the epidermis and dermis after they have committed to the melanocyte fate. These findings suggest that neurofibromin plays an important role in the specification of melanocytes within the glial lineage and may help design therapeutic options for treating NF1-related hyper-pigmentation in the future.
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