Incomplete intestinal development is a common gastrointestinal complication in neonates, yet the factors that control the late stages of intestinal development are unclear. Here, Michael Verzi and colleagues uncover a key role for the transcription factor YY1 in intestinal morphogenesis in mice (p. 3711). They demonstrate that Yy1 expression in the developing endoderm is required for the correct formation of villi – the structures that extend into the intestinal lumen. In particular, the extension of villi, rather than the initiation of villogenesis, is compromised in Yy1 mutants. Transcriptomic analyses reveal that genes associated with mitochondrial function are perturbed in Yy1 mutants. In line with this, the authors report that Yy1 loss leads to defective mitochondrial morphology. The researchers further demonstrate that oxidative phosphorylation genes are upregulated at the time of villus growth, and that mitochondrial inhibitors can block villus formation in explant cultures, suggesting that aerobic respiration is required for the late stages of intestinal development. Finally, the authors show that patients presenting with necrotizing enterocolitis, which is thought to be caused by incomplete intestinal development, exhibit reduced expression of YY1 target genes and oxidative phosphorylation genes. In summary, these findings highlight a clear link between metabolism and organogenesis.
