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M L Lamoreux

Publications and source records attributed to M L Lamoreux.

At least 37 records · Page 2Linked to original sources
PubMed1994

Molecular basis of mouse microphthalmia (mi) mutations helps explain their developmental and phenotypic consequences.

Mutations in the mouse microphthalmia (mi) gene affect the development of a number of cell types including melanocytes, osteoclasts and mast cells. Recently, mutations in the human mi gene (MITF) were found in patients with Waardenburg Syndrome type 2 (WS2), a dominantly inherited syndrome associated with hearing loss and pigmentary disturbances. We have characterized the molecular defects associated with eight murine mi mutations, which vary in both their mode of inheritance and in the cell types they affect. These molecular data, combined with the extensive body of genetic data accumulated for murine mi, shed light on the phenotypic and developmental consequences of mi mutations and offer a mouse model for WS2.

Alleles↗
PubMed1993

Postnatal ocular expression of tyrosinase and related proteins: disruption by the pink-eyed unstable (p(un)) mutation.

Ocular pigmentation in the mouse occurs primarily postnatally as a result of the melanization of neural crest-derived melanocytes. Using immunologic and biochemical techniques, we demonstrate that in normal mice the expression of tyrosinase and the related proteins TRP-1 and TRP-2, rises during the first week of life, remains elevated for a week, and then steadily declines to low levels by adulthood. Sucrose gradient density centrifugation demonstrates that tyrosinase, TRP-1 and TRP-2 are present in high molecular weight forms in the eyes of wild-type mice. The normal time course is disrupted in mice carrying the pink-eyed unstable (p(un)) mutation at the P-locus, a model for tyrosinase-positive albinism in man. Tyrosinase and TRP-2 are present at wild-type levels in the eyes of p(un)/p(un) mice at birth, but, rather than rising, their levels rapidly decline over the first week of life. TRP-1 is almost undetectable, even at birth. High molecular weight complexes could not be detected in eyes of p(un)/p(un) mice. Our results suggest that postnatal ocular melanogenesis in the mouse presents an attractive model for the study of the orderly expression and action of the proteins involved in eumelanin synthesis, and that the p(un) mutation disrupts this temporally controlled process.

Albinism↗
PubMed1993

Pathogenesis of the platinum (cp) mutation, a model for oculocutaneous albinism.

The platinum mutation at the C (albino) locus in the mouse is a potential model for oculocutaneous albinism in humans other than type IA (tyrosinase-negative) albinism. Although tissues from mice homozygous for the mutation display substantial tyrosinase activity, cutaneous and ocular pigmentation is severely restricted in affected animals. Using specific antipeptide antisera, we demonstrate that ocular extracts from wild-type mice contain two isoforms of tyrosinase bearing either the amino-terminal PEP5 epitope or the carboxy-terminal PEP7 epitope. The latter isoform participates in a high-molecular-weight complex detectable on sucrose density gradients. In platinum mice, antiserum to the PEP7 epitope fails to recognize any protein species, and the high-molecular-weight form of tyrosinase is not detectable. Our results support a key role for this high-molecular-weight complex in melanogenesis, and suggest that mutations that interfere with the ability of tyrosinase to participate in a multimeric complex may be a cause of oculocutaneous albinism in people.

Albinism, Oculocutaneous↗
PubMed1993

Ocular pathology in mice with a transgenic insertion at the microphthalmia locus.

A DNA insertional mutation at the microphthalmia locus (mi) in a transgenic mouse has been developed and given the allele symbol of mitg (Krakowsky et al., 1993). Mice homozygous for this transgene have eyes markedly reduced in size and relatively unpigmented. In this study, we examined the morphology of these eyes using light and electron microscopy. Transgenic homozygous (mitg/mitg) animals have a structurally normal choroid which lacks melanocytes but contains occasional leukocytes. The elastica of Bruch's membrane is absent except in an occasional site. The retinal pigmented epithelium (RPE) appears dramatically abnormal. It displays cellular heterogeneity, residual basal infoldings and apical microvilli, rare and immature melanosomes, and numerous cilia-like structures. Occasionally, cells of the RPE appear to have extruded into or from the choroid. The photoreceptor cells are devoid completely of outer segments and partially of inner segments. Numerous active macrophages are present between the amelanotic RPE and neuro-retina and also within the vitreous body. The anterior uveal tract is underdeveloped and hypomelanotic. This new microphthalmia model exhibits ocular pathology with similarities and differences to other mutations and the mi (microphthalmia) locus.

Alleles↗
PubMed1989

Isolation, chromosomal mapping, and expression of the mouse tyrosinase gene.

Using a human tyrosinase cDNA probe, we have isolated mouse tyrosinase genomic clones and used them to map the mouse tyrosinase locus and to analyze the promoter sequence of the tyrosinase gene. Southern blot analyses of DNA from somatic cell hybrids, interspecies backcross mice, and albino deletion mice have revealed that the locus for mouse tyrosinase resides at or near the albino locus on mouse chromosome 7. There were three TATA-elements, but only one CAT-element, and the CAT-element appeared to be paired with the third TATA-element, located at the position farthest upstream. Mouse tyrosinase mRNA is approximately 2.4 Kb in size. The amount of tyrosinase mRNA reflects the levels of tyrosinase activity in normal melanocytes and Cloudman S-91 melanoma cell line.

Albinism↗
PubMed1988

Animal models of an acquired pigmentary disorder--vitiligo.

Vitiligo appears to be a complex disorder that involves a melanocyte dysfunction and/or an autoimmune response. Further investigations of the animal models described in this report, and the less well-studied models that exist, is needed to clarify the mechanisms of this disorder. Three additional animal lines which appear potentially to be excellent animal models for vitiligo are: the Barred Plymouth Rock chicken which exhibits periodic degenerating melanocytes presumably due to a cytotoxic agent (Bowers et al, 1986), the White Leghorn chicken which exhibits preprogrammed melanocyte autophagocytosis (Jimbow et al, 1974), and the Duroc pig which exhibits spontaneous tumor regression and depigmentation (Hordinsky, personal communication). These numerous animal studies must be undertaken with the understanding that the specific etiologies and characteristics differ among these animal models and that each model represents only a facet of the complex condition, vitiligo. To unravel the complexity of this syndrome, the insightful correlation of the results of many investigators working with multiple model systems is required.

Animals↗
PubMed1987

Genetic controls over melanocyte differentiation: interaction of agouti-locus and albino-locus genetic defects.

Tyrosinase activities and dopachrome conversion activity were evaluated in extracts made from skins of 6-day-old mice that were mutant at the agouti and albino loci. Dopa oxidase (DO) activity of tyrosinase in fully pigmented (C/C) mice is reduced in extracts made from skins of yellow 6-day-old mice as compared to those of black mice. Dopachrome conversion (DC) activity is absent from skin extracts of normal yellow mice and is present in normal black mice. DC activity is a characteristic of a separate enzyme which has been called dopachrome conversion factor or dopachrome oxidoreductase. We measured the dopa oxidase activity and dopachrome conversion activity in skin extracts of yellow mice and black mice that were mutant at the albino (C) locus. Extracts made from extreme-dilution (ce/ce) mice do not have DO activity. Those from yellow extreme-dilution mice do not have DC activity, while those from black, extreme-dilution mice do. The DO and DC activities that characterize skin extracts made from platinum (cp/cp) yellow mice are similar to those of platinum black mice. These observations suggest possible mechanisms by which the functions controlled by the agouti and albino loci interact to control melanogenesis.

Albinism↗
PubMed1986

Genetic controls over activities of tyrosinase and dopachrome conversion factor in murine melanocytes.

We evaluated the three catalytic activities of tyrosinase and one activity of dopachrome conversion factor (DCF) in extracts made from skins of 6-day-old yellow and nonyellow mice. At least one of the catalytic activities of tyrosinase and of DCF correlate with the color of pigment being produced in the hair follicles of the mice. We use these data to evaluate existing hypotheses about the mechanism of the interacting genetic controls over melanogenesis.

Animals↗
PubMed1986

A mouse model for vitiligo.

As the result of a long search for a depigmenting mouse that could serve as a model for the study of vitiligo, we have located a strain that arose from the C57BL/6J. Its provisional genetic designation is C57BL/6J Ler-vit/vit. This vitiligo mouse has congenital dorsal and ventral white spots (piebaldism) as well as progressive replacement of pigmented hairs by white hairs with each spontaneous molt or after plucking. The lack of pigment is due to the absence of melanocytes from the amelanotic hair follicles and epidermis. As in human beings and the Smyth chicken model, there is also diminution of ocular pigment. Reciprocal skin transplants between C57BL/6J and vitiligo mice, and transplants into nude mice, suggest a programmed pigment cell death in the vitiligo mice. Like human beings with vitiligo, maximally depigmented vitiligo mice have a decreased contact sensitivity response in comparison to age-matched C57BL/6J controls. The resistance to injected B16 melanomas is lowered. Vitiligo mice show no signs of premature aging. Already at this early stage in the study of this new animal model, there are findings that open a range of new approaches to the study and treatment of patients with vitiligo and melanomas.

Animals↗
PubMed1983

New regulatory factors for melanogenesis: developmental changes in neonatal mice of various genotypes.

The biosynthesis of melanin occurs through sequential steps known as the Mason-Raper pathway. The initial steps are the conversion of tyrosine to dihydroxyphenylalanine (dopa) and of dopa to dopaquinone by the enzyme tyrosinase (EC 1.10.3.1). Until recently it was assumed that once these first two conversions were completed, the subsequent reactions occurred spontaneously. However, studies with mouse melanoma cells in culture revealed that subsequent steps in the pathway are also regulated. In this report, we demonstrate that these steps are also regulated in skins of fetal and newborn mice. The specific activities of the regulatory factors change during the first week after birth and differ in mice of different genotypes. The findings provide new insights into genetic and developmental regulation of the pigmentary system in mammals.

Albinism↗
PubMedDate not supplied

Transposable elements controlling genetic instabilities in mammals.

It is proposed that the instabilities in gene action of some alleles at certain loci in the mouse (e.g., a, c, H-2 Mi, p, pe, T, Va, W), which do not seem to conform to traditional hypotheses of gene action, are better interpretable in the light of modern studies of transposable DNA elements (insertion sequences and transposons of prokaryotic organisms; controlling elements of maize; transposable controlling elements of Drosophila). Some phenotypic evidence in the mouse in support of this hypothesis is presented for the a, Mi, p, and W loci, which affect pigmentation.

Animals↗