The Pigmentation Pathway
a brief illustraion of some genes involved in the pigmentation pathway
This webpage is part of a series on Dog Coat Color Genetics and was last updated on April 2, 2010 by Sheila Schmutz
The pigmentation pathway shares many genes with other biochemical pathways. Therefore mutations in some of these genes which affect coat color, might also affect neurological function, immunological function, fertility, etc. Yet another pathway which can be affected is the appetite pathway.
photo courtesy of G. Barsh, Stanford
This is a section of a mouse embryo at 13.5 days of gestation which illustrates that the melnocytes are migrating down from the neural crest derived cells along the spinal column and brain. It is not surprising that dogs of many breeds have missing pigment on a spot on their chest or a toe........these are the last places that pigment cells migrate in the dog. A lack of pigment in these spots isn't really inherited, it more likely means the dam had a cold for a few days during the gestational period. Many "Breed Standards" allow for a small white chest spot, which is certainly appropriate.
Two of the genes involved early in the pathway are Endothelin receptor B (EDNRB) and its ligand, Endothelin 3 (EDN3). At this stage the cells are barely beginning to differentiate into either neural precursor cells or pigment precursor cells. In the horse, a mutation in EDNRB is the cause of the Overso pattern of white spotting. In the homozygote, the foal is completely white and lacking nerves to the gut region which causes it to die within a few days of birth. During gestation it can develop normally since it is not relying on its gut for digestion. Nutrients are delivered to it pre-digested by its dam.
Early in melanoblast differentiation another pair of genes becomes important. KIT is the receptor and its ligand is now called KIT ligand (KITLG), but was previously known as Mast Cell Growth Factor (MGF). Mutations in KIT cause the common domestic pig to be white, really one big white spot. Mutations in KITLG cause mice called "steel" and cattle called "roan". In both mice and cattle, some homozygous individuals are infertile. Mast cells are also important in immunological function.
The diagram above illustrates some of the genes that are involved in pigmentation once the melanocyte has differentiated. Melanocyte Stimulating Hormone (MSH) and Agouti Signalling Peptide (ASIP) are both ligands which could bind to Melanocortin 1 Receptor (MC1R). In some dogs only one or the other binds because of mutations in MC1R or ASIP and in some dogs banded hairs occur because of alternate binding of MSH and ASIP during hair development, in a pattern most commonly called sable in the dog. In yet other dogs, mutations in the promoter region of ASIP cause dogs to bind MSH in one part of the body and ASIP in another, such as the Gordon Setter, an example of a black-and-tan dog.
The next series of genes causes the eumelanin produced when MSH binds or the phaeomelanin produced when ASIP binds to be "diluted" or appear more pale. These genes include Tyrosinase (TYR) which has been found to cause albinism in many species but thus far not proven in dogs, Dopachromome Tautomerase (DCT), called slatey in the mouse. Some people also refer to Tyrosinase Related Protein 1 (TYRP1) as a diluter gene because it causes the eumelanin to be brown instead of black. I've always had a hard time with that personally, because dilute black to me is grey, not brown.
There are other genes involved in the pigmentation pathway. Some mouse researchers would include a hundred or more in this category, but this gives a sampling of some of the major genes involved.
For example, a mutation, or likely mutations, in the MLPH gene causing the dilution of black to gray or blue as its called in many breeds or from brown to pale brown. MLPH is involving in ratcheting the pigment up into the hairs and is not expressed within the melanocyte.
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