DEVELOPMENTAL EXPRESSION OF THE MOUSE MOTTLED AND TOXIC MILK GENES SUGGESTS DISTINCT FUNCTIONS FOR THE MENKES-AND-WILSON-DISEASE COPPER TRANSPORTERS

Menkes disease and Wilson disease are human disorders of copper transp ort caused by mutations in distinct genes encoding similar copper-tran sporting P-type ATPases, These genes are expressed in different adult tissues in patterns reflecting disease manifestations. The mouse homol ogues for the Menkes (MNK) and Wilson (WND) disease genes are the mott led (Atp7a) and toxic milk (Atp7b) genes, respectively, Using RNA in s itu hybridization we describe the distribution of mottled and toxic mi lk transcripts during mouse embryonic development, The mottled gene is expressed in all tissues throughout embryogenesis and is particularly strong in the choroid plexuses of the brain. Mottled expression in th e liver is in contrast to the prior observation of absent or very low expression in the adult liver, Expression of the toxic milk gene is si gnificantly more delimited, with early expression in the central nervo us system, heart and liver, Later in gestation, toxic milk transcript is clearly seen in the liver, intestine, thymus and respiratory epithe lium including nasopharynx, trachea and bronchi, In lung, toxic milk e xpression is restricted to bronchi, while mottled expression is diffus e, Hepatic expression of both toxic milk and mottled is in the parench yma, as opposed to blood cells, These results suggest that the mottled gene product functions primarily in the homeostatic maintenance of ce ll copper levels, while the toxic milk gene product may be specificall y involved in the biosynthesis of distinct cuproproteins in different tissues.