Perinatal liver sympathetic innervation governs body size

Authors
Bobo-Jimenez, Veronica, Gomila, Silvia, Lapresa, Rebeca, Agulla, Jesus, Angibaud, Julie, Sanchez-Moran, Irene, Delgado-Esteban, Maria, González-Rodriguez, Agueda, Fernández-Jaén, Alberto, Ramos-Cabrer, Pedro, Nägerl, U. Valentin, Bolaños, Juan P., Almeida, Angeles


Lab
Bilbao

Journal
Communications Biology

Abstract
Perinatal failure in the growth hormone (GH)-insulin-like growth factor-1 (IGF-1) axis causes impaired body growth and central and autonomous neurodevelopmental disorders. However, whether a primary neurodevelopmental disorder causes organ misinnervation as a contributing factor in growth retardation is elusive. To interrogate this, here we generated a late embryonic neural-specific cdc20 homolog 1 (Cdh1) knockout mouse model, which exhibited a primary delay in early postnatal brain development. These mice displayed an intact GH-releasing hormone (GHRH)-GH-hepatic GH receptor (GHR) pathway despite a body growth retardation that could be reversed by IGF-1 administration in the early postnatal life. Mechanistically, liver sympathetic misinnervation impaired signal transducers and activators of transcription 5 (STAT5) phosphorylation, required for liver IGF-1 biosynthesis and release. We also report decreased blood levels of IGF-1 in a patient harboring a pathogenic mutation in Cdh1 that causes neurodevelopmental and growth delay. Taken together, these findings demonstrate that a primary neurodevelopmental defect disrupts sympathetic hepatic innervation, leading to a GH-independent growth retardation, thus establishing a positive feedback loop that propagates the disease presentation. A primary neurodevelopmental disorder controls liver IGF-1 secretion to boost organismal growth through a GH pathway-independent. Hepatic sympathetic misinnervation causes liver steatosis and fibrosis, leading to impaired GHR-JAK2-STAT5 pathway and IGF1 biosynthesis.

Keywords/Topics
Developmental disorders; Molecular neuroscience

BIOSEB Instruments Used:
Grip strength test (BIO-GS4)

Source :

https://www.nature.com/articles/s42003-026-09880-9

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