Sensory nerve-derived signaling coordinates oropharyngeal structural organization that supports suckling and vocalization in neonatal mice.

Proper oropharyngeal function is essential for suckling, feeding, and speech, and relies on the coordinated development of the palate, oropharyngeal musculature, and the cranial nerves that control them. Disruption of this integration leads to severe neonatal complications. However, how neuromuscular architecture is developmentally coordinated to support oropharyngeal function remains unclear. Using single-cell and spatial transcriptomics, we identify trigeminal nerve-derived GDF11 as a crucial regulator of soft palatal muscle architecture that acts through cranial neural crest-derived perimysial cells and is mediated by Akt-FoxO1-Thbs3 signaling to establish muscle structural integrity and bilateral continuity. To assess its functional relevance in vivo, we employ a battery of physiological assays to evaluate oropharyngeal function in neonatal mice and find that sensory neuron-specific Gdf11 deletion recapitulates soft palatal deformities and associated oropharyngeal dysfunction observed in individuals carrying GDF11 mutations, including impaired suckling, reduced oropharyngeal motor efficacy, and abnormal vocalizations. Pharmacological activation of AKT partially restores soft palatal muscle organization and ameliorates associated physiological deficits in Gdf11 mutant mice. Collectively, these findings demonstrate that sensory nerve-derived trophic signaling is indispensable for coordinated oropharyngeal morphogenesis and function, and establish a pre-clinical framework for the therapeutic approach targeting neuromuscular integration in congenital oropharyngeal disorders.