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Identification of ligand-receptor pairs that drive human astrocyte development
Anna J Voss1, Samantha N Lanjewar1, Maureen M Sampson1
1Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
Abstract:
Extrinsic signaling between diverse cell types is crucial for nervous system development. Ligand binding is a key driver of developmental processes. Nevertheless, it remains a significant challenge to disentangle which and how extrinsic signals act cooperatively to affect changes in recipient cells. In the developing human brain, cortical progenitors transition from neurogenesis to gliogenesis in a stereotyped sequence that is in part influenced by extrinsic ligands. Here we used published transcriptomic data to identify and functionally test five ligand-receptor pairs that synergistically drive human astrogenesis. We validate the synergistic contributions of TGFβ2, NLGN1, TSLP, DKK1 and BMP4 ligands on astrocyte development in both hCOs and primary fetal tissue. We confirm that the cooperative capabilities of these five ligands are greater than their individual capacities. Additionally, we discovered that their combinatorial effects converge in part on the mTORC1 signaling pathway, resulting in transcriptomic and morphological features of astrocyte development. Our data-driven framework can leverage single-cell and bulk genomic data to generate and test functional hypotheses surrounding cell-cell communication regulating neurodevelopmental processes.
Insights
Five key ligands (TGFβ2, NLGN1, TSLP, DKK1, BMP4) were found to cooperatively drive human astrocyte development by acting on the mTORC1 pathway, advancing our understanding of nervous system development.
Area of Science:
- Neuroscience
- Developmental Biology
- Cell Signaling
Background:
- Extrinsic cell signaling is vital for nervous system development, but understanding cooperative ligand actions is challenging.
- Cortical progenitor cells in the human brain undergo neurogenesis and gliogenesis influenced by extrinsic ligands.
Purpose of the Study:
- To identify and functionally test ligand-receptor pairs that synergistically drive human astrogenesis.
- To investigate the cooperative mechanisms of extrinsic signals in astrocyte development.
Main Methods:
- Utilized published transcriptomic data to identify potential ligand-receptor pairs.
- Functionally validated five key ligands (TGFβ2, NLGN1, TSLP, DKK1, BMP4) in human cerebral organoids (hCOs) and primary fetal tissue.
- Analyzed the convergence of combinatorial effects on signaling pathways like mTORC1.
Main Results:
- Identified and validated five ligands (TGFβ2, NLGN1, TSLP, DKK1, BMP4) that synergistically promote human astrogenesis.
- Demonstrated that the combined effect of these ligands exceeds their individual contributions.
- Showed that these ligands converge on the mTORC1 signaling pathway, influencing astrocyte transcriptomic and morphological development.
Conclusions:
- A data-driven framework was developed to generate and test hypotheses on cell-cell communication in neurodevelopment.
- The findings reveal critical cooperative signaling interactions essential for human astrocyte development.
- This study elucidates the synergistic roles of specific ligands in regulating astrocyte differentiation via the mTORC1 pathway.
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