Mary A. Bedell

A molecular basis for classic blond hair color in Europeans

Hair color differences are among the most obvious examples of phenotypic variation in humans. Although genome-wide association studies (GWAS) have implicated multiple loci in human pigment variation, the causative base-pair changes are still largely unknown. Here we dissect a regulatory region of the KITLG gene (encoding KIT ligand) that is significantly associated with common blond hair color in northern Europeans. Functional tests demonstrate that the region contains a regulatory enhancer that drives expression in developing hair follicles. This enhancer contains a common SNP (rs12821256) that alters a binding site for the lymphoid enhancer-binding factor 1 (LEF1) transcription factor, reducing LEF1 responsiveness and enhancer activity in cultured human keratinocytes. Mice carrying ancestral or derived variants of the human KITLG enhancer exhibit significant differences in hair pigmentation, confirming that altered regulation of an essential growth factor contributes to the classic blond hair phenotype found in northern Europeans.

Analysis of Hypomorphic KitlSl Mutants Suggests Different Requirements for KITL in Proliferation and Migration of Mouse Primordial Germ Cells

Abstract Germ cell development in mice is initiated when a small number of primordial germ cells (PGCs) are set aside from somatic cells during gastrulation. In the subsequent 4 to 5 days, PGCs enter the hindgut, undergo a directed migration away from the hindgut into the developing gonads, and undergo a massive increase in cell number. It is well established that Kit ligand (KITL, also known as stem cell factor and mast cell growth factor) is required for the survival and proliferation of PGCs. However, there is little information on a direct role for KITL in PGC migration. By comparing the effects of multiple Kitl mutations, including two N-ethyl-N-nitrosourea-induced hypomorphic mutations, we were able to distinguish stages of PGC development that are preferentially affected by certain mutations. We provide evidence that the requirements for KITL in proliferation are different in PGCs before and after they start migrating, and different levels of KITL function are required to support PGC proliferation and migration. This study illustrates the usefulness of an allelic series of mutations to dissect developmental processes and suggests that these mutants may be useful for further studies of molecular mechanisms of KITL functions in gametogenesis.

Effects of spontaneous KitlSteel mutations on survival and red blood cells of mice

Kit ligand (Kitl), which is a member of the helical cytokine superfamily, is encoded by the Steel (Sl) locus of mice and is essential for the development of hematopoietic cells, germ cells, and melanocytes. A large series of KitlSl alleles has been described, including some that arose spontaneously and others that were induced by either chemical or radiation mutagenesis. Here we describe the nucleotide sequence alterations in two spontaneous KitlSl alleles. The KitlSl-18R allele has a point mutation that introduces a premature termination codon, and the encoded protein is expected to be null functionally. The KitlSl-5R allele has an in-frame deletion that results in deletion of amino acids at position 31 and 32 of Kitl. While both mutations exert severe effects on blood cells and survival of homozygous mice, these effects are slightly milder than those of a previously characterized spontaneous deletion allele, KitlSl-gb. Examination of the survival of compound heterozygotes provided strong genetic evidence that the KitlSl-18R and KitlSl-5R mutants are null functionally for mouse survival.

Mutagenesis of the mouse genome

Foreword M. Justice From the Atomic Age to the Genome Project M.J. Justice Chemical mutagenesis of the mouse genome: an overview J.-L. Guenet Effects of male germ-cell stage on the frequency, nature, and spectrum of induced specific-locus mutations in the mouse L.B. Russell Allelic mutations of the sodium channel SCN8A reveal multiple cellular and physiological functions M.H. Meisler, N.W. Plummer, D.L, Burgess, D.A. Buchner, L.K. Sprunger Towards a mutant map of the mouse - new models of neurological, behavioural, deafness, bone, renal and blood disorders S. Rastan, T. Hough, A. Kierman, A. Erven, I.C. Gray, S. Voeling, A. Isaacs, H. Tsai, M. Strivens, R. Washbourne, C. Thornton, S. Greenaway, M. Hewitt, S. McCormick, R. Selley, C. Wells, Z. Tymowska-Lalanne, P. Roby, P. Mburu, D. Rogers, D. Kelsell, J.-L. Guenet, K.P. Steel, S. Sheardown, N. Spurr, I. Gray, J. Peters, P.M. Nolan, A.J. Hunter, S.D.M. Brown Implementing large-scale ENU mutagenesis screens in North America A.T. Clark, D. Goldowitz, J.S. Takashi, M.H., Viterna, S.M. Siepka, L.L. Peters, W.N. Frankel, G.A. Carlson, J. Rossant, J.H. Nadeau, M.J. Justice Genetic mapping and ENU mutagenesis D.R. Beier, B.J. Herron The Mouse Phenome Project M.A. Bogue, S.C. Grubb Genetically altered mice: phenotypes, no phenotypes, and Faux phenotypes S.W. Barthold Visualizing the laboratory mouse: capturing phenotype information M. Strivens, J.T. Eppig