Lalonde, R. | Search bioRxiv

bioRxiv2025

MiR-34a deficiency enhances nucleic acid sensing and type I IFN signaling in a mouse model of Alzheimer's disease

MiR-34a is implicated in aging, cell senescence, inflammation, and neurodegenerative diseases. In order to investigate the role of miR-34a in Alzheimers disease (AD), we produced an AD mouse model, Tg-SwDI mice, with whole body/constitutive miR-34a knockout (KO). MiR-34a KO improved long-term memory in Tg-SwDI mice, which was associated with decreases in the ratio of insoluble A{beta}42 to A{beta}40 and with increases in soluble and insoluble A{beta}40 in the cerebral cortex. Anti-Iba1 immunofluorescence revealed increases in activated microglia. Bulk RNA-sequencing of the hippocampus followed by a gene set enrichment analysis (Enrichr) identified "cellular response to type I interferon" and "type I interferon signaling pathway" as the most prominent gene sets in miR-34a KO Tg-SwDI mice compared to miR-34a wild-type Tg-SwDI mice. Many interferon-stimulated genes (ISGs) that characterize interferon responsive microglia (IRM) were upregulated in miR-34a KO Tg-SwDI mice. MiR-34a knockdown strongly enhanced ISGs expression in TLR7 ligand-stimulated BV2 microglia. These results suggest that miR-34a inhibits the transition of microglia to the IRM state that may modulate synaptic and cognitive functions in neurodegenerative diseases and aging.

neuroscience↗

bioRxiv2024

CO-OPTION OF NECK MUSCLES SUPPORTED THE VERTEBRATE WATER-TO-LAND TRANSITION

A major event in vertebrate evolution was the separation of the skull from the pectoral girdle and the acquisition of a functional neck, transitions which required profound developmental rearrangements of the musculoskeletal system. The neck is a hallmark of the tetrapod body plan and allows for complex head movements on land. While head and trunk muscles arise from distinct embryonic mesoderm populations, the origins of neck muscles remained elusive. Here, we combine comparative embryology and anatomy to reconstruct the mesodermal contribution to neck evolution. We demonstrate that head/trunk-connecting muscle groups have conserved mesodermal origins in fishes and tetrapods and that the neck evolved from muscle groups present in fishes. We propose that expansions of mesodermal populations into head and trunk domains during embryonic development underpinned the emergence and adaptation of the tetrapod neck. Our results provide evidence for exaptation of archetypal muscle groups in ancestral fishes, which were co-opted to acquire novel functions adapted to terrestrial lifestyle.

evolutionary biology↗