GIGYF1-disturbed IGF-1R recycling: a potential contributor to autism spectrum disorder pathogenesis?
Mengen Xing, … , Qing Zhang, Weihong Song
Mengen Xing, … , Qing Zhang, Weihong Song
Published October 3, 2022
Citation Information: J Clin Invest. 2022;132(19):e163553. https://doi.org/10.1172/JCI163553.
View: Text | PDF
Commentary

GIGYF1-disturbed IGF-1R recycling: a potential contributor to autism spectrum disorder pathogenesis?

Abstract

Autism spectrum disorder (ASD) is a highly variable and heritable neurodevelopmental disease (NDD) with strong genetic underpinnings. In this issue of the JCI, Chen et al. analyzed 2 previously reported, large-scale sequenced ASD cohorts and reported that GIGYF1 is the second most mutated among ASD risk genes. In this issue of the JCI, Chen et al. used a conditional mouse model combined with molecular technologies based on human genetic analyses to determine the critical role of GIGYF1 in ASD. GIGYF1-deficiency affected the recycling of IGF-1R, thereby suppressing the IGF-1R/ERK signaling pathway. Disruption of GIGYF1 in the developing mouse brain led to social deficits and cognitive impairments. These findings extend our understanding of ASD pathogenesis and provide an avenue for developing potentially effective preventions and treatments for patients with ASD.

Authors

Mengen Xing, Qing Zhang, Weihong Song

×

Figure 1

A model for GIGYF1-disrupted IGF-1R signaling as a cause for reduced neocortical neurogenesis.

Options: View larger image (or click on image) Download as PowerPoint
A model for GIGYF1-disrupted IGF-1R signaling as a cause for reduced neo...
Under normal conditions, GIGYF1 regulates the IGF-1R/ERK signaling pathway, likely through the clathrin-dependent endocytosis and Rab4-mediated recycling of IGF-1R. GIGYF1 forms a complex with GRB10 and IGF-1R and facilitates the internalization of IGF-1R into early endosomes. The complex then transports to Rab4-positive recycling endosomes, and the internalized IGF-1R is recycled to the plasma membrane. IGF1 binds to IGF-1R on the plasma membrane and activates the downstream ERK signaling pathway, which regulates the cell cycle. Normal proliferation, migration, and differentiation of neural progenitor cells (NPCs) are essential for the proper architecture and function of the cerebral cortex. In the scenario of GIGYF1 haploinsufficiency, the GIGYF1-regulated recycling of internalized IGF-1R to the plasma membrane is reduced. Lower IGF-1R levels on the cell surface reduces IGF-1R/ERK signaling and perturbs the cell cycle dynamics. The disrupted IGF-1R/ERK signaling pathway and cell cycle dynamics may account for the disturbance of NPC proliferation and differentiation caused by GIGYF1 deficiency. Finally, disturbed NPC proliferation and differentiation reduce neocortical neurogenesis, which may underlie ASD pathogenesis.