Perinatal liver sympathetic innervation governs body size

Bobo-Jimenez V(#)(1)(2), Gomila S(#)(1)(2), Lapresa R(1)(2), Agulla J(1)(2),
Angibaud J(3), Sanchez-Moran I(1)(2), Delgado-Esteban M(1)(2),
González-Rodriguez A(4)(5), Fernández-Jaén A(6), Ramos-Cabrer P(7)(8), Nägerl
UV(3)(9), Bolaños JP(1)(2)(10), Almeida A(11)(12).

Author information:
(1)Institute of Functional Biology and Genomics, CSIC, University of Salamanca,
Salamanca, Spain.
(2)Institute of Biomedical Research of Salamanca, University Hospital of
Salamanca, University of Salamanca, CSIC, Salamanca, Spain.
(3)Interdisciplinary Institute for Neuroscience, University of Bordeaux, CNRS
UMR, Bordeaux, France.
(4)Sols-Morreale Institute of Biomedical Research, CSIC-UAM, Madrid, Spain.
(5)Centro de Investigación Biomédica en Red de Diabetes y Enfermedades
Metabólicas Asociadas (CIBERDEM), Madrid, Spain.
(6)Departamento de Neurologia Infantil, Hospital Universitario Quironsalud,
Universidad Europea de Madrid, Madrid, Spain.
(7)CIC biomaGUNE, Basque Research and Technology Alliance (BRTA), Donostia-, San
Sebastián, Spain.
(8)Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
(9)Institut für Anatomie und Zellbiologie, Universitätsmedizin Göttingen,
Georg-August-Universität, Göttingen, Germany.
(10)Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento
Saludable (CIBERFES), Madrid, Spain.
(11)Institute of Functional Biology and Genomics, CSIC, University of Salamanca,
Salamanca, Spain. .
(12)Institute of Biomedical Research of Salamanca, University Hospital of
Salamanca, University of Salamanca, CSIC, Salamanca, Spain. .
(#)Contributed equally

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.

© 2026. The Author(s).

DOI: 10.1038/s42003-026-09880-9
PMCID: PMC13129087
PMID: 41826417 [Indexed for MEDLINE]

Conflict of interest statement: Competing interests: The authors declare no
competing interests.

Auteurs Bordeaux Neurocampus