Developmental Loss of Astrocytic QKI Compromises Postnatal Central Nervous System Homeostasis

Rocío I. Zorrilla Veloz, BS (Advisor: Jian Hu, PhD)

             Astrocytes are the predominant glial cell type in the central nervous system (CNS) and are essential for maintaining its homeostasis through regulation of neurotransmitter clearance, metabolic support, blood-brain barrier integrity, and ion and water equilibrium. While the importance of these homeostatic functions is well established, the molecular regulators that coordinate astrocyte homeostasis are still not fully understood. The RNA-binding protein Quaking (QKI) has emerged as a key regulator of glial biology; more recently it’s been implicated in astrocyte biology. However, whether astrocytic QKI coordinates the molecular programs required to maintain CNS homeostasis and neurological function remain unclear. To further investigate this, we generated an inducible astrocyte-specific Qki knockout mouse model.

             Astrocyte-specific deletion of Qki resulted in progressive severe neurological dysfunction and histological abnormalities within the CNS. Transcriptomic profiling identified coordinated dysregulation of genes involved in lipid metabolism, glutamate and amino acid transport and astrocyte-associated homeostatic functions. These transcriptional programs are required for normal astrocyte physiology, and its disruption under QKI loss induces neurological dysfunction and cellular abnormalities. Together, these findings highlight QKI as a critical regulator of astrocyte function and CNS integrity.

Advisory Committee:

• Jian Hu, PhD, Chair
• Daniel Frigo, PhD
• David Grosshans, MD, PhD
• Hyun Kyoung Lee, PhD
• Hyun Eui Kim, PhD
• Vihang Narkar, PhD