Assessing the role of the autism risk gene Gigyf1 in astrocytic regulation of postnatal brain development in mice

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impaired social communication and repetitive behavior. In the United States, 1 in 44 children are diagnosed with ASD, and this prevalence is rising according to the U.S. Centers for Disease Control and Prevention. ASD research efforts indicate a multitude of rare genetic variants converge on biological pathways associated with synaptic function and connectivity. The identification of causal genetic variants provides a starting point for a new mechanistic understanding of ASD. Therefore, functional examination of ASD risk genes can provide opportunities to uncover mechanisms underlying ASD etiologies. One step forward in this direction is understanding gene function in model systems.

This study will focus on GRB10-Interacting GYF Protein 1 (GIGYF1), a high-confidence risk gene according to the SFARI Gene database. Studies in several independent cohorts have identified likely gene-disruptive mutations in the GIGYF1 gene in autistic individuals. According to a recent report, GIGYF1 is the second-most mutated gene among ASD risk genes¹. However, knowledge of GIGYF1 function in brain development is scarce. Recent studies have reported that GIGYF1 is required for translational repression in human cell lines^2-6. Specifically, GIGYF1 facilitates the translational repression of cytokine mRNAs, a critical regulatory mechanism of inflammatory signaling.

Disruptions in mRNA regulation are also implicated in neurodevelopmental conditions such as ASD. However, GIGYF1 involvement in ASD is relatively new, and there is a dearth of knowledge about the expression patterns and functions of GIGYF1 in brain development. Unbiased single-cell RNA sequencing data from human and mouse brain samples indicate that human GIGYF1 mRNA is abundant in astrocytes during early postnatal life. Astrocytes play an active role in several key processes of neuronal function including the formation of synapses, dendrite arborization and pruning of supernumerary synapses during the critical period of postnatal brain development. However, the disruptive role of astrocytes in postnatal brain function in ASD is unknown.

To study the function of GIGYF1 in astrocytes at postnatal stages, Dilek Colak and colleagues generated a conditional transgenic Gigyf1 mouse line. In their preliminary studies, spatial and temporal disruption of mouse Gigyf1 in astrocytes led to behavioral deficits associated with ASD in heterozygous mice, suggesting that astrocytic Gigyf1 regulates neuronal activity.

In the current project, Colak’s lab plans to further study the behavioral phenotypes caused by haploinsufficiency or loss-of-function of astrocytic Gigyf1 in mice and to assess the impact of astrocytic Gigyf1 deficiency on synaptic function and plasticity in vivo. To gain mechanistic insight into the astrocytic function of Gigyf1, they plan to determine mRNAs and biological pathways that are regulated by Gigyf1 in mouse astrocytes in vivo.

This project will define, for the first time, the role of this ASD risk gene in astrocytic regulation of postnatal brain development. In doing so, it aims to provide novel insights into the etiology of ASD. While it is widely accepted that altered translation is linked to ASD, posttranscriptional regulation in glial cells during postnatal development in both neurotypical and ASD brains has been ignored. Thus, this project’s findings will significantly advance our knowledge of astrocytic mRNA regulation in the context of ASD.

References

1. Chen G.D. et al. J. Clin. Invest. 132 (2022) PubMed
2. Peter D. et al. Gene. Dev. 33, 1355-1360 (2019) PubMed
3. Peter D. et al. Gene Dev. 31, 1147-1161 (2017) PubMed
4. Ruscica V. et al. Nucleic Acids Res. 47, 7035-7048 (2019) PubMed
5. Tollenaere M.A.X. et al. Cell Rep. 26, 3511-3521 (2019) PubMed
6. Weber R. et al. Cell Rep. 33 (2020) PubMed