Catherine Van Raamsdonk
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Cancer cell metastasis. Neural crest cell development. Molecular analysis of melanocytes and melanoma cells from mouse models: transcriptomics, bioinformatics, proteomics. Primary cell culture, FACS, Immunohistochemistry/Immunofluorescence. Therapeutics and signaling pathways in melanoma.
Graduate Student Supervision
Doctoral Student Supervision (Jan 2008 - May 2019)
The glabrous skin, which includes, the tail, the footpads, the nose and the ears, of the mouse retain melanocytes in the dermis, the hair follicles of the epidermis and the interfollicular regions of the epidermis. Given that melanocytes in humans are exclusively found in the epidermis and hair follicles, the epidermis of the glabrous skin of the mouse can be a functional model in the study of melanocytes. A dominant N-ethyl-N-nitrosourea (ENU) mutagenesis screen of C3HeB/FeJ mice at the National Research Center for Environment and Health (GSF) in Germany recovered two mutants, Und3 and Und4. These mice are characterized by a reduction in pigmentation that is localized to the middle regions of the tail, with the base and tip retaining pigmentation. Mapping and sequencing revealed single base pair changes in Adamts9. The mutations in Adamts9 create null alleles and Adamts9, expressed in the epidermis, is required for melanoblast migration in the tail at 18.5 dpc. A conditional knockout of Adamts9 suggests that the hypopigmentation is due to the loss of Adamts9 in melanocytes, but not keratinocytes. Terminal amine isotopic labeling of substrates (TAILS) was used to identify changes in potential cleavage processes between Adamts9Und4/+ and wildtype mice. Several candidates, associated with the stratum basale, were found to be significantly different between the wildtype and the mutant proteomes. These candidates are involved in the regulation of cytoplasmic cell structure (Filamin-A, Filamin-B, beta-tubulin 4A and alpha-tubulin 1C), maintaining the structural organization of cells within the extracellular matrix (Plectin, Desmoplakin, Perisotin and Vimentin) and communication between cells (Type XII collagen, Type VII collagen, Fibrillin-1, Fibronectin, Tenascin and Biglycan). These findings suggest that Adamts9 is essential for the appropriate migration of melanoblasts in the developing embryo and immediately after birth. Additionally, this protease is likely involved in mouse pigmentation by maintaining an environment in the stratum basale that supports the migration of melanoblasts in the epidermis through the activation of proliferation pathways during development. Supplementary video material is available at: http://hdl.handle.net/2429/52938
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.
Master's Student Supervision (2010 - 2018)
Somatic mutations in the homologous human oncogenes GNAQ, and GNA11, are frequently found in ocular melanomas of the uvea, blue nevi of the dermis, and melanocytic neoplasias of the central nervous system (CNS), but rarely in cutaneous melanoma located in the epidermis (0.3%). The most common mutation found in GNAQ/11 is the amino acid substitution Q209L in the Ras-like GTPase domain. It causes complete or partial loss of intrinsic GTPase activity thereby locking the protein in a constitutively active form. To compare the downstream signal transduction effects of GNAQQ²⁰⁹L on melanocytes in different locations such as the dermis, the epidermis, ears, eyes and CNS, the mutant gene was conditionally knocked-in to the ubiquitous Rosa26 locus in mice to normalize gene expression among melanocytes. When expression of GNAQQ²⁰⁹L was induced in melanoblasts (immature melanocytes) during embryogenesis, the mice exhibit hyperpigmentation in the dermis of the tail, footpad, trunk, and ears beginning at a young age, with non-cutaneous melanocyte overgrowth in the inner ear and CNS, and metastatic uveal melanoma in older animals. In older adult mice, a progressive loss of melanocytes occurred in the inter-follicular epidermis, which could explain the lack of GNAQ mutations in human cutaneous melanomas located in the epidermis. When expression of GNAQQ²⁰⁹L was induced in mature melanocytes in adult, some of the above phenotypes such as hyperpigmentation in the dermal skin and uveal track thickening in the eyes were observed. When expression of GNAQQ²⁰⁹L was induced in bipotential Schwann cell precursors, there was a decrease in the number of melanoblasts, suggesting that GNAQQ²⁰⁹L blocks the production of melanoblasts from Schwann cell precursors.Altogether, I developed the first mouse uveal melanoma model driven by oncogenic mutant GNAQQ²⁰⁹L gene. These mice display all three types of lesions driven by constitutively active GNAQ in human: blue nevi, uveal melanoma, and invasive melanocytic neoplasias of the CNS. I show that the downstream effects of GNAQQ²⁰⁹L on melanocytes are strongly dependent upon cellular context, as seen in the differences presented in the epidermis, dermis, uveal and CNS melanocytes.
- Melanocyte development in the mouse tail epidermis requires the Adamts9 metalloproteinase. (2018)
Pigment cell & melanoma research,
- Rapid melanoma induction in mice expressing oncogenic BrafV600E using Mitf-cre. (2017)
Pigment cell & melanoma research,
- Gnaq and Gna11 in the Endothelin Signaling Pathway and Melanoma. (2016)
- Oncogenic G Protein GNAQ Induces Uveal Melanoma and Intravasation in Mice. (2015)
- Update from the 2013 International Neurofibromatosis Conference. (2014)
- Differential effects of neurofibromin gene dosage on melanocyte development. (2013)
- Genetic interactions between neurofibromin and endothelin receptor B in mice. (2013)
- Links between Schwann cells and melanocytes in development and disease. (2013)
- Mutation of GNAQ in a cytologically unusual choroidal melanoma in an 18-month-old child. (2013)
- Adam10 haploinsufficiency causes freckle-like macules in Hairless mice. (2012)
- Mutations in GNA11 in uveal melanoma. (2010)
- Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. (2009)
- Hereditary hair loss and the ancient signaling pathways that regulate ectodermal appendage formation. (2009)
- Independent regulation of hair and skin color by two G protein-coupled pathways. (2009)
- Dorsoventral patterning of the mouse coat by Tbx15. (2004)
- Effects of G-protein mutations on skin color. (2004)
- Genetics of dark skin in mice. (2003)
- Disruption of an imprinted gene cluster by a targeted chromosomal translocation in mice. (2001)
- Optimizing the detection of nascent transcripts by RNA fluorescence in situ hybridization. (2001)
- Dosage requirement and allelic expression of PAX6 during lens placode formation. (2000)
Development, 127 (24), 5439-5448