Disturbances in developmental pathways leading to a neurological disorder of genetic origin, “leaner,” in mice

Abstract

A linkage relationship between the leaner gene, la, and esterase gene, El, was described. The recombination frequency between these genes was found to be 3.84%. Developmental pathways leading to neurological disorders in the leaner mutant were investigated. It was found that the thymidine uptake by the brain, liver and spleen of the mutant mice was significantly lower than that of their normal sibs. There was a good correlation between the lower thymidine uptake and the reduced number of mitotic figures in the liver and cerebellum. Reduced thymidine uptake was found to occur between day 5 and day 6 of postnatal age; it persisted as long as there was a sufficient amount of DNA synthesis (or cell division). It was shown that there was a faster breakdown of DNA synthesized in the mutants, but that this faster breakdown was an irregular event, occurring in association with the late stage of the affliction. It was pointed out that the faster breakdown of DNA was not the basis for the neurological disorders. A lower uridine and leucine uptake was occasionally observed in the mutant organs at the late stage of affliction. This was pointed out as being associated with the atrophy of the organs. The level of RNA and protein showed a similar tendency. It was shown that a developmental lag in the total nitrogen level of the mutants was not a consistent phenomenon, and that this lag was independent from the behavioral abnormalities. It was shown that the metabolism of RNA, protein, and esterase in the mutant organs was relatively normal during the early stage of affliction in spite of the drastic reduction in the rate of DNA synthesis and cell division.