| HuC and HuD are neuron‑specific members of the ELAV/ELAVL RNA‑binding protein family that recognize U‑ and AU‑rich elements in target transcripts and regulate post‑transcriptional gene expression programs involved in neuronal differentiation, synaptic activity, and responses to stress. Both proteins display a conserved modular organization with three RNA recognition motifs separated by a flexible hinge region; functional dissection of HuC shows that all three RRMs together with the hinge are required to bind regulatory RNA elements and to control alternative splicing of neuronal pre‑mRNAs, demonstrating that the complete RNA‑binding interface and its conformational flexibility participate in splice site selection. HuD binds to 3′ UTR regions of growth‑ and plasticity‑related mRNAs and increases their stability and translation, with validated targets including APP and BACE1 mRNAs and the long noncoding RNA BACE1AS, which itself stabilizes BACE1 mRNA; coordinated binding to these transcripts raises APP and BACE1 expression and promotes processing of APP toward elevated Aβ production. HuD also associates with broader sets of coding and noncoding RNAs linked to neuronal signaling, learning, and memory and modulates both mRNA half‑life and splicing, so that its expression level influences the abundance of multiple Alzheimer’s disease–related proteins and synaptic regulators in human neurons. HuD expression increases along the neuronal lineage under the control of proneural transcription factors and remains high in mature neurons, and manipulation of HuD levels in human iPSC‑derived neurons alters global translation patterns and dendritic spine features, consistent with a role in shaping neuronal proteomes. In neuroblastoma and other tumors with neuronal characteristics, HuD is overexpressed and binds mRNAs encoding regulators of mTORC1 signaling, notably GRB10 and the ER‑resident protein ARL6IP1; HuD‑dependent stabilization of these targets reduces mTORC1 activity, enhances autophagy, and attenuates apoptosis under stress, conditions that favor tumor cell survival. Neuroblastoma xenograft models with reduced HuD expression show decreased tumor growth, linking its RNA‑binding activity to cancer cell viability, and strong HuC/D immunoreactivity is widely used as a diagnostic marker to identify neuroblastic and neuroendocrine tumors because of the strict neuronal lineage specificity of these proteins. HuC and HuD act as central components of neuron‑restricted RNA regulons, integrating sequence‑specific binding via their RRMs with control of mRNA stability, splicing, and translation in pathways that govern neurodevelopment, synaptic maintenance, and survival under stress. |
