Date of Award
2026
Document Type
Thesis
Degree Name
Doctor of Philosophy (PhD)
Thesis Advisor
Shai Shaham
Abstract
Astrocytes are essential regulators of nervous system development, homeostasis, and function. Beyond their well-established roles in synapse formation, metabolic support, and neural circuit modulation, astrocytes are increasingly recognized as dynamic participants in behavior regulation and neurological disease. Despite their importance, the developmental logic by which astrocytes acquire their identity and functional properties remains incompletely understood. In particular, how distinct developmental programs coordinate to establish astrocyte identity, and how immature glial cells transition into fully functional astrocytes, are central unresolved questions in neurobiology. In this thesis, I investigate the developmental mechanisms that establish astrocyte identity and function using the astrocyte-like Caenorhabditis elegans CEPsh glia. Leveraging their defined lineage, I generated a lineage-resolved single-cell transcriptomic atlas of early developing CEPsh glia to dissect the temporal transcriptional programs underlying their development. I show that CEPsh glia arise from distinct embryonic lineages but converge onto a shared early transcriptional state. This convergence is accompanied by the acquisition of radial glia-like features, suggesting a conserved intermediate state that supports nervous system assembly. Following this convergent phase, CEPsh glia undergo a second developmental transition characterized by extensive morphological remodeling and transcriptional maturation, marked by the upregulation of genes associated with mature astrocyte function. I further identify the homeodomain transcription factor CEH-43, a homolog of vertebrate DLX genes, as a key regulator of CEPsh glia development. CEH-43 is required for both the establishment of early glial identity and the activation of astrocyte-specific gene expression programs. CEH-43 binds to conserved regulatory regions of astrocyte-related genes and plays a predominant role in the initiation of astrocyte gene expression. Notably, DLX1/2, the orthologs of CEH-43, are expressed in a small subset of mammalian astrocytes, suggesting a potential conserved role of DLX proteins in astrocyte development. Together, these findings support a two-phase model of CEPsh glia development, in which lineage convergence establishes a shared identity, followed by a maturation program that confers functional specialization. This work provides a conceptual framework for understanding how astrocyte identity is built through sequential developmental programs and suggests that key aspects of this process may be evolutionarily conserved. In addition to the main findings, the Appendix includes complementary studies that expand on the themes of glial development. These include method development in lineage- resolved transcriptomics, identification of additional regulators of glial development, and exploratory investigations into cis-regulatory elements for pan-glial gene expression regulation. Together, these studies provide supporting context and technical foundations that further inform the conclusions of this thesis. Overall, this work establishes CEPsh glia as a powerful model for understanding fundamental principles governing the establishment of astrocyte identity and function during nervous system development.
License and Reuse Information
This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 4.0 International License.
Recommended Citation
Liu, Simin, "Astrocyte Identity and Function Acquisition During Nervous System Development in C. Elegans" (2026). Student Theses and Dissertations. 860.
https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/860
Comments
A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy