Regulation and Function of the Rna-Binding Protein Khsrp During Neuronal Development, Regeneration and Axonal Injury Response

Axons, which extend long distances from neuronal cell bodies, rely on localized mRNA translation to swiftly respond to extracellular stimuli and physiological states. This work investigates the mechanism underlying the RNA-binding protein KHSRP’s, axonal mRNA translation and regulatory pathways involved in neuronal growth and regeneration. Our results indicate that KHSRP deletion in mice leads to upregulation of growth-associated mRNAs linked to neuronal morphology and function, resulting in increased axon growth and altered memory consolidation. Indicating a critical role for KHSRP in neuronal development and function through post-transcriptional regulation (Chapter 2). Additionally, we show there is a rapid increase in axonal KHSRP levels after peripheral nerve injury which occurs via local translation of Khsrp mRNA that is stimulated by a Ca2+ --> PERK --> eIF2aPS51 mechanism. We demonstrate that increased KHSRP levels after injury also promote the decay of KHSRP target mRNAs impeding neuronal growth and regeneration (Chapter 3). Finally, we introduce an autocrine signaling mechanism involving REG3A and KHSRP, which maintains axonal KHSRP levels post-injury. REG3A induced calcium release and subsequent Khsrp translation contribute to slowed axon growth, with Reg3a depletion accelerating regeneration (Chapter 4). Collectively, our work elucidates the complex regulatory networks of axonal mRNA translation, highlighting KHSRP as a key modulator of neuronal response to injury and regeneration.