Unique Splicing of Lrp5 in the Brain: A New Player in Neurodevelopment and Brain Maturation

Abstract

Low-density lipoprotein receptor-related protein 5 (LRP5) is a constitutively expressed receptor with observed roles in bone homeostasis, retinal development, and cardiac metabolism. However, the function of LRP5 in the brain remains unexplored. This study investigates LRP5’s role in the central nervous system by conducting an extensive analysis using RNA-seq tools and in silico assessments. Two protein-coding Lrp5 transcripts are expressed in mice: full-length Lrp5-201 and a truncated form encoded by Lrp5-202. Wt mice express Lrp5-201 in the liver and brain and do not express the truncated form. Lrp5−/− mice express Lrp5-202 in the liver and brain and do not express Lrp5-201 in the liver. Interestingly, Lrp5−/− mouse brains show full-length Lrp5-201 expression, suggesting that LRP5 has a role in preserving brain function during development. Functional gene enrichment analysis on RNA-seq unveils dysregulated expression of genes associated with neuronal differentiation and synapse formation in the brains of Lrp5−/− mice compared to Wt mice. Furthermore, Gene Set Enrichment Analysis highlights downregulated expression of genes involved in retinol and linoleic acid metabolism in Lrp5−/− mouse brains. Tissue-specific alternative splicing of Lrp5 in Lrp5−/− mice supports that the expression of LRP5 in the brain is needed for the correct synthesis of vitamins and fatty acids, and it is indispensable for correct brain development.