Abnormalities in neural crest-derived melanocyte development are associated with several hereditary hypopigmentation disorders, including Waardenburg syndrome (WS, OMIM#193500). Elucidation of the genetic pathway coordinating neural crest-derived melanocyte development will provide genes to assess as candidates in hypopigmentation disorders. Hepatocyte Growth Factor/Scatter Factor (HGF) signaling through the tyrosine kinase receptor MET is capable of promoting the proliferation, increasing the motility and maintaining high tyrosinase activity and melanin synthesis of melanocytes in vitro 1 . In addition, transgenic mice that ubiquitously overexpressed HGF demonstrate hyperpigmentation in the skin and leptomenigenes and can induce melanoma formation in vivo 2, 3 . To investigate if HGF/MET signaling is essential for neural crest-derived melanocyte development, embryos with a targeted MET null mutation (Met -/-) and transgenic embryos ubiquitously overexpressing HGF were analyzed. In both the loss and gain of function mutant embryos, melanoblast number and location were unaffected prior to 11 days post coitus (p. c.). However, after 12 days p.c. Met -/- embryos exhibited a spatially restricted loss of trunk-derived melanoblasts, and HGF transgenic embryos exhibited ectopically localized melanoblasts. Addition of HGF to an in vitro neural crest culture increased melanoblast number, permitted differentiation into pigmented melanocytes, promoted melanoblast survival, and signaled through Steel factor (SLF) responsive cells. These results demonstrate that HGF/MET signaling is essential for melanocyte development and implicate these genes as candidates for human neural crest disorders such as WS.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Intramural Research (Z01)
Project #
1Z01HG000095-02
Application #
6109013
Study Section
Special Emphasis Panel (LGDR)
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
National Human Genome Research Institute
Department
Type
DUNS #
City
State
Country
United States
Zip Code