Neural-specific Cdh1 loss impairs postnatal sympathetic liver innervation, leading to STAT5 signaling dysfunction, reduced IGF-1 biosynthesis, and body growth retardation.
Does a primary neurodevelopmental disorder cause organ misinnervation as a contributing factor in growth retardation?
A primary neurodevelopmental defect disrupts sympathetic hepatic innervation, leading to a GH-independent growth retardation via impaired STAT5 phosphorylation and IGF-1 biosynthesis.
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.
Bobo-Jiménez et al. (Sat,) conducted a other in Growth retardation. Neural-specific Cdh1 knockout vs. Wild-type (Nes-WT) was evaluated on Body weight and IGF-1 levels. Neural-specific Cdh1 loss impairs postnatal sympathetic liver innervation, leading to STAT5 signaling dysfunction, reduced IGF-1 biosynthesis, and body growth retardation.