Dynamically expressed single ELAV/Hu orthologue elavl2 of bees is required for learning and memory

Abstract

Changes in gene expression are a hallmark of learning and memory consolidation. Little is known about how alternative mRNA processing, particularly abundant in neuron-specific genes, contributes to these processes. Prototype RNA binding proteins of the neuronally expressed ELAV/Hu family are candidates for roles in learning and memory, but their capacity to cross-regulate and take over each other’s functions complicate substantiation of such links. Honey bees Apis mellifera have only one elav/Hu family gene elavl2, that has functionally diversified by increasing alternative splicing including an evolutionary conserved microexon. RNAi knockdown demonstrates that ELAVL2 is required for learning and memory in bees. ELAVL2 is dynamically expressed with altered alternative splicing and subcellular localization in mushroom bodies, but not in other brain regions. Expression and alternative splicing of elavl2 change during memory consolidation illustrating an alternative mRNA processing program as part of a local gene expression response underlying memory consolidation.

Regulation of the Alternative Neural Transcriptome by ELAV/Hu RNA Binding Proteins

“…This may suggest that although Drosophila fne knockouts exhibit only mild defects on their own, Fne actually harbors features of an ancestral ELAV/Hu member. Consistent with this, very recent studies of the single honeybee member ELAVL2 (which shares the Drosophila Fne microexon), reveals highly complex alternative splicing and variable levels of nuclear and cytoplasmic proteins in different settings (Ustaoglu et al, 2021). This is consistent with the notion that a single ancestral ELAV/Hu locus might combine functions that are separated into multiple family members in other species.…”

“…Therefore, there is a hierarchy of nuclear ELAV/Hu RBPs in Drosophila that can be regulated dynamically by splicing. This may relate to the ancestral state of insect genomes, which may have only an Fne-type family member that executes both nuclear and cytoplasmic functions ( Samson, 2008 ; Ustaoglu et al, 2021 ).…”

1-L Transcription in Alzheimer’s Disease

“…ELAVL2 interacts with hnRNP K to control neuronal differentiation, and regulates axonogenesis via post-transcriptional interaction with genes involved in neurodevelopment, transport, localization, and cytoskeleton, including GAP43 [ 110 ]. Apis mellifera (bees) have only one elav/Hu family gene elavl2, expression and alternative splicing of which is required for learning and memory [ 111 ]. Regulation of transcript expression by ELAVL2 has been shown to be critical for neuronal function and clinically relevant to autism [ 112 ], and ELAV1/HUR and ELAV2/HUB are critical for the occurrence of MMP-9 mRNA stabilization upon neuronal activation [ 113 ].…”

“…In the nucleus, the Aβ peptide suppresses TF ZHX2, which promotes transcription of PTEN phosphatase, which directly inhibits the PI3K-Akt pathway. Aβ suppresses KAT2B/PCAF, which stimulates the gluconeogenic program; Aβ also promotes the major histone methyltransferase NSD2 (H3K36me2), associated with increased NADPH levels and decreased ROS levels; and Aβ post-transcriptionally supports RBP ELAV2/HUB, which is required for learning and memory in bees [ 111 ] ( Figure 5 ).…”

“…According to the presented model, DCP2 and ELAVL2/HuB are suppressed. DCP2 is a key component of an mRNA-decapping complex, and ELAVL2/HuB may be required for learning and memory [ 111 ]. Their repression ( Figure 6 ) can significantly destabilize post-transcriptional “signal noise suppression”, leading to neuronal dysfunction and memory loss.…”