Document Type

Dissertation - University Access Only

Award Date

1997

Degree Name

Doctor of Philosophy (PhD)

Department / School

Biology and Microbiology

Abstract

lleles at the murine agouti locus dictate whether black pigment (eumelanin) or yellow pigment (phaeomelanin) is to be synthesized by melanocytes in hair bulbs (Silvers, 1979). Agouti protein (AP), a product of the agouti (a) locus, in addition to directly antagonizing cx.-melanocyte stimulating hormone (cx.-MSH) at the level of MSH receptor (MCl-R) on melanocytes (Takeuchi et al., 1989; Lu et al., 1994), may also cause an imbalance in the relative proportions of at least two of the melanotropins/melanocortins, mono-acetyl-cx.-MSH (mMSH) and its precursor des-acetyl-a.-MSH ( dMSH), thus leading to phaeomelanogenesis and perhaps other features of the lethal yellow syndrome (L YS) - obesity, diabetes, infertility, immuno suppression, etc., in the yellow mutant mice (Ay/-, Avy/-) of agouti locus (Bray et al., 1994). Either AP or dMSH by competitively binding to MCl-R on the hair follicle melanocytes may bring about a truncated adenylate cyclase signaling cascade in terms of lowered cAMP, decreased tyrosinase activities (both tyrosine hydroxylase (TH) and dopa oxidase (DO)) and finally phaeomelanin rather than eumelanin. Objectives of the present study were to test the antagonistic actions of both AP as well as dMSH with mMSH for MCI-R using a Bl6 melanoma cell-line as an experimental model. Melanogenic parameters measured included - cAMP, TH, DO activities, and melanin content. Results show that AP at higher concentrations than mMSH does indeed antagonize MCl-R causing truncated adenylate cyclase and thus lowered cAMP tum over, reduced TH and DO activities as well as decreases in melanin content, indicating its ability to divert eumelanin synthesis to phaeomelanin synthesis. dMSH on the other hand does not bring about a decline in cAMP nor any dose-dependent decline in mMSH-induced TH activities in B 16 cells. dMSH does indeed possess melanogenic properties like that of mMSH in tenns of its ability to enhance cAMP, TH and DO activities and total melanin content. These data suggest: 1) AP directly antagonizes mMSH at the level ofMCl-R. 2) AP does not appear to cause an imbalance in melanocortins, because such an imbalance does not induce phaeomelanogenesis. Reciprocal serum injection experiments reveal that the serum of Ay/a mice when injected into the plucked dorsal surface of a/a mice, bring about a decline in the TH activities. This indicates that there are factors in the yellow serum which act to reduce the tyrosinase activities. However, this is not attributable to the actions of AP as it is shown to be absent in the serum.

Library of Congress Subject Headings

Mice -- Genetics Melanins -- Synthesis Pigments (Biology)

Format

application/pdf

Number of Pages

133

Publisher

South Dakota State University

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