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The Retinoid Hypothesis posits that abnormal retinoic acid signaling leads to the formation of diaphragmatic hernias. Our goal is to better understand diaphragm development and the etiology of CDH. To achieve this goal, we first performed single\u2010cell RNA sequencing analysis of the developing diaphragm, then generated a conditional retinoic acid receptor dominant negative knock\u2010in to inhibit retinoic acid signaling in the mesenchyme of the developing diaphragm. Our single\u2010cell RNA sequencing analysis revealed 10 distinct cell populations in the developing diaphragm, with mesenchymal cells being the primary expresser of CDH and retinoic acid signaling\u2010related genes. Transgenic inhibition of mesenchymal retinoic acid signaling in the developing diaphragm caused hernias in 100% of embryos, recapitulating the hallmarks of CDH. 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