La-related protein 6 controls ciliated cell differentiation

Abstract

BackgroundLa-related protein 6 (LARP6) is an evolutionally conserved RNA-binding protein. Vertebrate LARP6 binds the 5′ stem-loop found in mRNAs encoding type I collagen to regulate their translation, but other target mRNAs and additional functions for LARP6 are unknown. The aim of this study was to elucidate an additional function of LARP6 and to evaluate the importance of its function during development.MethodsTo uncover the role of LARP6 in development, we utilized Morpholino Oligos to deplete LARP6 protein in Xenopus embryos. Then, embryonic phenotypes and ciliary structures of LAPR6 morphants were examined. To identify the molecular mechanism underlying ciliogenesis regulated by LARP6, we tested the expression level of cilia-related genes, which play important roles in ciliogenesis, by RT-PCR or whole mount in situ hybridization (WISH).ResultsWe knocked down LARP6 in Xenopus embryos and found neural tube closure defects. LARP6 mutant, which compromises the collagen synthesis, could rescue these defects. Neural tube closure defects are coincident with lack of cilia, antenna-like cellular organelles with motility- or sensory-related functions, in the neural tube. The absence of cilia at the epidermis was also observed in LARP6 morphants, and this defect was due to the absence of basal bodies which are formed from centrioles and required for ciliary assembly. In the process of multi-ciliated cell (MCC) differentiation, mcidas, which activates the transcription of genes required for centriole formation during ciliogenesis, could partially restore MCCs in LARP6 morphants. In addition, LARP6 likely controls the expression of mcidas in a Notch-independent manner.ConclusionsLa-related protein 6 is involved in ciliated cell differentiation during development by controlling the expression of cilia-related genes including mcidas. This LARP6 function involves a mechanism that is distinct from its established role in binding to collagen mRNAs and regulating their translation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13630-017-0047-7) contains supplementary material, which is available to authorized users.

Maternal Larp6 controls oocyte development, chorion formation and elevation

“…Recent data raise the possibility of broader function for Larp6. In Xenopus, a morpholino loss of function study has implicated LARP6 in ciliogenesis, a process occurring widely across eukaryotes (Manojlovic et al, 2017). However, our MZlarp6 double mutants show none of the strong defects reported in zebrafish ciliogenesis mutants (Zhao and Malicki, 2007).…”

Discovery and evaluation of inhibitor of LARP6 as specific antifibrotic compound

“…A few functions of LARP6, other than regulation of type I collagen, have been described. They include regulation of muscle differentiation and integrin expression in differentiating myoblasts and differentiation of ciliated cells in embryonic development 60–63 . However, these functions do not involve binding of collagen mRNAs, therefore, it is not clear if they will be affected by LARP6 binding inhibitors.…”

Acheron/Larp6 Is a Survival Protein That Protects Skeletal Muscle From Programmed Cell Death During Development

“…Acheron is a phylogenetically conserved protein that plays a number of critical roles in both development and pathogenesis (Stavraka and Blagden, 2015). It is required for differentiation and cell survival in several lineages in vertebrates, including muscle, neurons, osteoblasts (Wang et al, 2009;Guo et al, 2017), and multi-ciliated cells (Manojlovic et al, 2017). It also confers a growth advantage for some tumors, such as triple-negative basal-like breast cancers, where it helps drive angiogenesis and invasiveness (Shao et al, 2012).…”