IGF2 acts downstream of Hippo signaling to regulate organ growth and restore liver regeneration in aging.

Zhenxing Zhong, Ruxin Jin, Yiting Zhong, Yawen Fu, Rui Zhu, Li Zhang, Zhihan Jiao, Fanhui Zhou, Lingdu Meng, Jiajie Zhu, Lingyan Zhang, Jian Wu, Rui Dong, Huirong Yang, Yanhui Xu, Kun-Liang Guan, Fei Lan, Yu Wang, Fa-Xing Yu

Institute of Pediatrics, Children's Hospital of Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, Qidong-Fudan Innovative Institution of Medical Sciences, the State Key Laboratory of Genetics and Development of Complex Phenotypes, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.Institute of Pediatrics, Children's Hospital of Fudan University, and the Shanghai Key Laboratory of Medical Epigenetics, Qidong-Fudan Innovative Institution of Medical Sciences, the State Key Laboratory of Genetics and Development of Complex Phenotypes, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China. · pubmed

Paper

Abstract

Precise regulation of organ size is essential for proper function, yet the underlying logic remains unclear. Here, we identify a Hippo-IGF2 signaling axis as a regulator of organ growth. During mouse liver development, Igf2 is highly expressed in fetal and neonatal hepatocytes to fuel rapid growth but is directly silenced by the Hippo signaling pathway at the postnatal stage, enforcing growth arrest and determining liver size. In contrast, chronic liver injury inactivates Hippo signaling and induces Igf2 expression, which is essential for regeneration. Notably, this regenerative response is defective in aged mice but can be restored by ectopic Igf2 expression. As a hormone, circulating IGF2 can compensate for local deficiencies in response to organ-restricted perturbations, whereas whole-body Hippo activation or Igf2 deletion results in small mice with miniature organs. Hence, the Hippo-IGF2 axis is a general regulator of growth and organ size during development and regeneration.

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Research summary

The paper claims that the Hippo-IGF2 signaling axis regulates organ size and that restoring IGF2 expression can rescue defective liver regeneration in aged mice. This is relevant to longevity research because it identifies a specific molecular mechanism (Hippo-IGF2) that fails during aging and demonstrates that bypassing this failure can restore regenerative capacity, addressing a root cause of age-related tissue dysfunction rather than just treating symptoms.

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