Rbm24 controls poly(A) tail length and translation efficiency of crystallin mRNAs in the lens via cytoplasmic polyadenylation

Abstract

Lens transparency is established by abundant accumulation of crystallin proteins and loss of organelles in the fiber cells. It requires an efficient translation of lens messenger RNAs (mRNAs) to overcome the progressively reduced transcriptional activity that results from denucleation. Inappropriate regulation of this process impairs lens differentiation and causes cataract formation. However, the regulatory mechanism promoting protein synthesis from lens-expressed mRNAs remains unclear. Here we show that in zebrafish, the RNAbinding protein Rbm24 is critically required for the accumulation of crystallin proteins and terminal differentiation of lens fiber cells. In the developing lens, Rbm24 binds to a wide spectrum of lens-specific mRNAs through the RNA recognition motif and interacts with cytoplasmic polyadenylation element-binding protein (Cpeb1b) and cytoplasmic poly(A)-binding protein (Pabpc1l) through the C-terminal region. Loss of Rbm24 reduces the stability of a subset of lens mRNAs encoding heat shock proteins and shortens the poly(A) tail length of crystallin mRNAs encoding lens structural components, thereby preventing their translation into functional proteins. This severely impairs lens transparency and results in blindness. Consistent with its highly conserved expression in differentiating lens fiber cells, the findings suggest that vertebrate Rbm24 represents a key regulator of cytoplasmic polyadenylation and plays an essential role in the posttranscriptional control of lens development.Rbm24 | lens | cataract | cytoplasmic polyadenylation | zebrafish

RNA-Binding Protein Rbm24 as a Multifaceted Post-Transcriptional Regulator of Embryonic Lineage Differentiation and Cellular Homeostasis

“…For example, both the N-terminal and C-terminal regions of Rbm24 are required for interaction with Stk38 kinase [ 29 ]. Although the N-terminal region of zebrafish Rbm24a does not directly interact with cytoplasmic polyadenylation element-binding protein 1b (Cpeb1b) and cytoplasmic poly(A)-binding protein 1l (Pabpc1l), its absence decreases the capacity of the C-terminal region to interact with these partners [ 20 ]. Thus, Rbm24 displays biochemical and functional conservation with respect to Rbm38, and its functionality in different cellular processes may be regulated through interaction with specific protein partners.…”

“…Loss of Rbm24 severely impairs heart development in zebrafish and mouse embryos [ 14 , 17 , 20 , 33 , 38 ]. Knockdown or knockout of rbm24a in zebrafish is sufficient to cause severe cardiogenic defects [ 14 , 20 , 33 ]. Although rbm24a morphants or mutants have a beating heart, blood is only transported back and forth between the ventricle and atrium.…”

“…Although rbm24a morphants or mutants have a beating heart, blood is only transported back and forth between the ventricle and atrium. This is due to the defective atrioventricular separation, which impairs blood circulation in the whole body [ 20 ]. In Rbm24 homozygous mutant mice, heart malformations, including defective ventricular septum, reduced myocardial compaction, dilated atria and abnormal atrioventricular endocardial cushions, become evident at E10.5, these are followed by growth retardation at subsequent stages and embryonic lethality at E13.5 [ 17 , 38 ].…”

“…It seems that vertebrate Rbm24 could be involved in nearly all aspects of post-transcriptional regulation. Most importantly, it functions as a key factor that regulates alternative splicing to establish the contractile function in developing cardiac and skeletal muscles [ 17 , 18 , 19 ], and plays an important role in cytoplasmic polyadenylation (CPA) to ensure the accumulation of crystallin proteins during lens fiber cell terminal differentiation [ 20 ]. There is thus accumulating evidence that Rbm24 acts as a multifaceted regulator to initiate cell differentiation through distinct mechanisms, which may vary in a tissue-specific and even a stage-specific manner.…”

Alternative Splicing of Cdh23 Exon 68 Is Regulated by RBM24, RBM38, and PTBP1

“…RBM24 is an RNAbinding protein that contains an RNA-recognition motif (RRM) and an alanine-rich low-complexity region. It has been shown that RBM24 regulates pre-mRNA alternative splicing as well as mRNA stability and translation [24,[29][30][31][32][33][34][35][36][37][38]. RBM24 is a major regulator of muscle-specific alternative splicing, and global Rbm24 inactivation affects cardiac development that eventually leads to embryonic death [24].…”