During late gestation, villi extend into the intestinal lumen to dramatically increase the surface area of the intestinal epithelium, preparing the gut for the neonatal diet. Incomplete development of the intestine is the most common gastrointestinal complication in neonates, but the causes are unclear. We provide evidence in mice that Yin Yang 1 (Yy1) is crucial for intestinal villus development. YY1 loss in the developing endoderm had no apparent consequences until late gestation, after which the intestine differentiated poorly and exhibited severely stunted villi. Transcriptome analysis revealed that YY1 is required for mitochondrial gene expression, and ultrastructural analysis confirmed compromised mitochondrial integrity in the mutant intestine. We found increased oxidative phosphorylation gene expression at the onset of villus elongation, suggesting that aerobic respiration might function as a regulator of villus growth. Mitochondrial inhibitors blocked villus growth in a fashion similar to Yy1 loss, thus further linking oxidative phosphorylation with late-gestation intestinal development. Interestingly, we find that necrotizing enterocolitis patients also exhibit decreased expression of oxidative phosphorylation genes. Our study highlights the still unappreciated role of metabolic regulation during organogenesis, and suggests that it might contribute to neonatal gastrointestinal disorders.
The authors declare no competing or financial interests.
N.K., M.S., S.J., K.D.W., A.Z., W.J.F., A.O.P., E.M.B. performed the research; N.K., M.S., S.J., K.D.W., O.J.S., D.L.G., J.X., E.M.B., N.G., E.W., M.P.V. interpreted data; N.K., M.S., M.P.V. drafted the manuscript; N.K. and M.P.V. conceived the study.
Work in the M.P.V. lab was supported by a grant from the National Institutes of Health (NIH) [R03DK099251] and the Human Genetics Institute of New Jersey. N.G. and M.P.V. were supported by the Rutgers Faculty Research Program. Work at the University of Michigan was funded by an NIH grant [R01 DK089933] and the University of Michigan Gastrointestinal Peptide Research Center. The E.W. lab was supported through NIH grants [R01 CA130893, R01 CA188096, R01 CA193970 and R01 CA163591]. This research was also supported by the Flow Cytometry Shared Resource of the Rutgers Cancer Institute of New Jersey [P30CA072720]. Deposited in PMC for release after 12 months.
Microarray datasets for Yy1f/f and Yy1f/f; Shh-cre small intestine are available at Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE85602) under accession number GSE85602.
Supplementary information available online at http://dev.biologists.org/lookup/doi/10.1242/dev.137992.supplemental
- Received March 23, 2016.
- Accepted August 25, 2016.