Maternal Dicer Knockout Impairs Growth and Gut Health in Nursing Wild-type Pups in Mice (P11-137-19)

Abstract

Abstract Objectives Background: Dicer catalyzes microRNA biogenesis. Administration of tamoxifen to heterozygous Dicer conditional knockout (KO) mice (Dicer + /-) deletes one Dicer allele (Dicer KO). Nanoparticles (exosomes) transfer microRNAs from donor cells to recipient cells. Humans absorb exosomes and microRNA cargos from milk. MicroRNAs regulate the expression of 60% of mammalian genes. Objectives: Assess whether the loss of microRNA biogenesis in lactating Dicer KO dams impairs growth and gut health in nursing wild-type pups. Methods Newborn pups from wild-type (WT) C57BL/6 breeders were fostered to synchronized Dicer + /- dams. Dams were injected with tamoxifen or vehicle (control). Additional controls included WT pups fostered to WT dams injected with tamoxifen or vehicle. Body weight gain and milk consumption were measured at timed intervals up to 21 days when pups were euthanized. Body fat accretion was assessed using NMR. Sections of the gastrointestinal tract were evaluated by histology analyses. The unpaired t-test was used for statistical analysis (tamoxifen vs. vehicle); P < 0.05 was considered statistically significant. Results Body weight and fat accretion in male and female pups nursed by Dicer KO dams was significantly lower than in vehicle controls at age 3 weeks (Figs. 1 and 2). Histology assessment revealed villous atrophy in the small intestine from pups nursed by Dicer KO dams compared to vehicle controls at age 3 weeks (Figs. 3–5). Tamoxifen administration did not elicit phenotypes in wild-type pups nursed by wild-type dams (not shown). Milk consumption was not significantly different between pups nursed by Dicer KO dams and controls (not shown). Conclusions Loss of microRNA biogenesis in lactating Dicer KO dams impairs growth and gut health in nursing wild-type pups. The quality of milk secreted by Dicer KO dams remains to be assessed. Funding Sources NIFA, NIH, Gerber Foundation, Gates Foundation, PureTech, Inc. and USDA Hatch and Multistate. J.Z. is a consultant for PureTech. Supporting Tables, Images and/or Graphs