TY - JOUR
T1 - AYY1-dependent increase in aerobic metabolism is indispensable for intestinal organogenesis
AU - Kumar, Namit
AU - Srivillibhuthur, Manasa
AU - Joshi, Shilpy
AU - Walton, Katherine D.
AU - Zhou, Anbo
AU - Faller, William J.
AU - Perekatt, Ansu O.
AU - Sansom, Owen J.
AU - Gumucio, Deborah L.
AU - Xing, Jinchuan
AU - Bonder, Edward M.
AU - Gao, Nan
AU - White, Eileen
AU - Verzi, Michael P.
N1 - Publisher Copyright:
© 2016. Published by The Company of Biologists Ltd.
PY - 2016/10/15
Y1 - 2016/10/15
N2 - 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.
AB - 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.
KW - Intestinal maturation
KW - Intestinal organogenesis
KW - Mouse
KW - Necrotizing enterocolitis
KW - Oxidative phosphorylation
KW - Villus
KW - YY1
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UR - http://www.scopus.com/inward/citedby.url?scp=84991810777&partnerID=8YFLogxK
U2 - 10.1242/dev.137992
DO - 10.1242/dev.137992
M3 - Article
C2 - 27802136
AN - SCOPUS:84991810777
SN - 0950-1991
VL - 143
SP - 3711
EP - 3722
JO - Development (Cambridge)
JF - Development (Cambridge)
IS - 20
ER -