International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)


Karen Fitch
Stanford University
279 Campus Drive
Beckman Center, B281
Stanford, CA 94305 USA

Co-Authors: 1)McGowan KA, 1)Van Raamsdonk CD, 2)Fuchs H, 2)Hrabé de Angelis M, 1)Barsh GS
Institutions: 1)Stanford University, 2)Institute of Experimental Genetics, GSF

Among nearly 100 mouse coat color mutations collected over the past century, those that cause dark hair by affecting Agouti signaling have identified key components of an important paracrine signaling pathway. Large-scale mutagenesis projects offer the potential to further the application of forward genetics, to determine if the collection of coat color mutations has been saturated, and potentially, to discover new genes that control melnaocyte homing to the intra vs. inter-follicular microenvironment.

We have characterized ten new ENU-induced dominant mutations that cause dark coat color (Dcc) or dark skin (Dsk), and therefore are likely to interfere with pigment switching or follicular homing of melanocytes, respectively. Each maps to a different position, with one of the Dsk and two of the Dcc mutants likely to represent new alleles of Egfr, Agouti, and Sox18. Double mutant studies between Sox18 and Agouti or Mc1r reveals that Sox18 is genetically upstream of the other two mutants, suggesting that Sox18 directly regulates Agouti transcription.

Using a melanocyte specific lacZ reporter transgene reveals two distinct classes of Dsk mutants, distinguished by whether melanocytes accumulate beneath the dermal-epidermal junction or within the interfollicular epidermis. In both cases, intrafollicular pigmentation is normal or increased, suggesting that instructive cues for follicular homing are acquired by developing pigment cells prior to visible pigment production.

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