Low‐density lipoprotein receptor‐related protein 6 regulates alternative pre‐mRNA splicing

Abstract

Low‐density lipoprotein receptor‐related protein 6 (LRP6) serves as a Wnt coreceptor. Although Wnt/LRP6 signalling is best known for the β‐catenin‐dependent regulation of target genes in tissue development and homeostasis, emerging evidence demonstrates the biological aspects of LRP6 beyond a Wnt coreceptor. Whether LRP6 modulates tissue development in a Wnt/β‐catenin signalling‐independent manner remains unknown. Using a model of striated muscle development, we observed that LRP6 was almost undetectable in proliferating myoblasts, whereas its expression gradually increased in the nucleus of myodifferentiating cells. During myodifferentiation, LRP6 modulated the muscle‐specific splicing of integrin‐β1D and consequent myotube maturation independently of the β‐catenin‐dependent Wnt signalling. Furthermore, we identified that the carboxy‐terminal serine‐rich region in LRP6 bond to the adenine‐rich sequence within alternative exon D (AED) of integrin‐β1 pre‐mRNA, and therefore, elicited AED inclusion when the spliceosome was recruited to the splice site. The interaction of LRP6 with the adenine‐rich sequence was sufficient to overcome AED exclusion by a splicing repressor, polypyrimidine tract binding protein‐1. Besides the integrin‐β1, deep RNA sequencing in different types of cells revealed that the LRP6‐mediated splicing regulation was widespread. Thus, our findings implicate LRP6 as a potential regulator for alternative pre‐mRNA splicing.

Melanotransferrin Functions as a Pro-Oncogenic WNT Agonist: A Yin-Yang Relationship in Melanoma with the WNT Antagonist and Metastasis Suppressor, NDRG1

“…Of note, LRP6 has been identified in the nucleus of normal and neoplastic cell-types where multiple effector functions have been reported. 45–47 The current studies demonstrate LRP6 and p-LRP6 (Ser1490) were significantly increased in the cytoplasmic (C) and nuclear (N) fractions of the MTf overexpression clones ( Figure 3e ). MTf overexpression also significantly increased nuclear β-catenin translocation and its cytoplasmic levels ( Figure 3e ).…”

LRP6 downregulation promotes cardiomyocyte proliferation and heart regeneration

“…26 In addition, we identified LRP6 as a potential splicing regulator in a muscle development model. 40 Here, we identified a critical role of LRP6 as an RNA-binding protein in the postnatal transition of cardiomyocyte proliferation. Lrp6 deficiency accelerated the degradation of Ing5 mRNA by directly binding the Ing5 transcript.…”

Immunocytochemical Analysis of Endogenous Frizzled-(Co-)Receptor Interactions and Rapid Wnt Pathway Activation in Mammalian Cells

“…Interestingly, FZD6–LRP6 complexes were mainly observed in the nucleus of PC-3 ( Figure 3 ). It has been shown that the soluble intracellular domains of surface receptors, such as FZDs and LRP6, can translocate to the cytoplasm and nucleus, where they could affect gene transcription in a β-catenin-dependent or -independent manner [ 27 , 28 ]. Consistent with the early detection of FZD6–LRP interactions, nuclear translocation of the downstream effector β-catenin was determined even within 5 min and increased linearly until 40 min ( Figure 3 ).…”