The Role of the Microenvironment on the Localization of Hair and Skin Nonuniform Pigmented Spots in Mice with a Targeted Mutation in the Endothelin B Receptor.

Abstract

In mammals, severe mutations in genes controlling melanocyte development, such as Mitf, which encodes a transcription factor, often result in the complete loss of pigmentation in the skin and eyes. However, null mutations in the gene encoding the EDNRB (endothelin B receptor) allow for the appearance of pigmented spots rostrally and caudally. In this study, we show that the microenvironment dictates the local appearance of these spots. Using transcriptomic profiling and in situ hybridization analyses, we find that in Ednrb-deficient embryos at embryonic day 11.5, a high expression level of KITL surrounds melanoblasts in the caudal but not the trunk region. A reduction in KITL/KIT function by genetic manipulation results in the complete loss of spots in the corresponding adults. Moreover, the intradermal injection of anti-KIT antibodies in the head region of EDNRB-deficient mice reduces hair pigmentation in the local spots during the secondary hair cycle. Furthermore, embryonic trunk explants from Ednrb-deficient embryos, which are generally unable to produce melanocytes, generate melanocytes after treatment with high-dose KITL, likely through the stimulation of MITF (microphthalmia-associated transcription factor). These findings underscore the significance of the microenvironment for the appearance and localization of pigment spots, highlighting the role of KITL as a key determinant of this microenvironment.