Loss of Function of the Circadian Clock Gene Period Promotes the Development of Intestinal Tumors in Aging Flies
Calvin K Chen, Mary A Roberts, F Rob Jackson, Robert N Salomon. Tufts Medical Center, Boston, MA; Tufts University School of Medicine, Boston, MA
Background: The fruit fly, D. melanogaster, is the most genetically tractable model organism. Histopathological analysis has rarely been used to study flies. We took protocols for light microscopy of tissue biopsies and applied them to flies. Despite millions of years of divergent evolution the intestinal tracts of humans and flies show many similarities. Both are lined by epithelial cells renewed by populations of stem cells. Flies typically live 8 to10 weeks under standard lab conditions. By age 4 weeks gut tumors form in a minority of flies and increase in incidence with age. Discovered in 1971 period (per) was the first gene shown to affect circadian behavior. Mammalian homologs of per have roles in cell cycle control and tumor development. We investigated the role of per on tumor development in aging flies.
Design: We studied three sets of 6 week old flies: 1) A commonly used strain of control flies (w1118) with the wild-type per gene 2) Flies bearing per01, a nonfunctional allele of per and 3) Transgenic flies bearing the per01 allele that carry a functional copy of per via the 13.2 (HA/C)16A per+ transgene. All flies were raised and processed for microscopy under identical conditions using standard techniques.
Results: Histological analysis of the flies revealed proximal gut tumors in 4%, 19% and 5% of control, per01 and rescue flies, respectively. Loss of function of per resulted in an approximate five-fold increase in the number of proximal gut neoplasms in 6 week old flies. Restoration of per function lowered the incidence of tumors to control levels (Table 1). Masses of dysplastic cells filled the proximal gut lumen as seen in transverse section (Fig.1A). Contrast with the regular cytoarchitecture of normal fly gut (Fig.1B).
|Intestinal Neoplasm||Total||% Tumor||Chi-Square|
|Per Rescue Flies||92||5.43%||0.415|