Ribosome-Mediated Specificity in Hox mRNA Translation and Vertebrate Tissue Patterning

Abstract

Historically, the ribosome has been viewed as a complex ribozyme with constitutive rather than regulatory capacity in mRNA translation. Here we identify mutations of the Ribosomal Protein L38 (Rpl38) gene in mice exhibiting surprising tissue specific patterning defects, including pronounced homeotic transformations of the axial skeleton. In Rpl38 mutant embryos, global protein synthesis is unchanged however the translation of a select subset of Homeobox mRNAs is perturbed. Our data reveal that RPL38 facilitates 80S complex formation on these mRNAs as a regulatory component of the ribosome to confer transcript-specific translational control. We further show that Rpl38 expression is markedly enriched in regions of the embryo where loss-of-function phenotypes occur. Unexpectedly, a ribosomal protein (RP) expression screen reveals dynamic regulation of individual RPs within the vertebrate embryo. Collectively, these findings suggest that RP activity may be highly regulated to impart a new layer of specificity in the control of gene expression and mammalian development.

Ribosomal biogenesis genes play an essential and p53-independent role in zebrafish pancreas development

“…One possibility is that individual assembly factors are expressed in a cell type-specific or tissue-restricted manner. A recent report using an Rpl38 mutant mouse described a previously unappreciated enrichment of Rpl38 expression during development in tissues that are affected by its loss (Kondrashov et al, 2011). This also appears to be the case for pes, where tissues with high-level pes expression, including brain, eye and pancreas, are those most severely affected in the pes mutant phenotype (Fig.…”

A ribosome-specialized translation initiation pathway is required for cap-dependent translation of vesicular stomatitis virus mRNAs

“…For example, during initiation on the CrPV IRES, the RNA must associate with rpL1 for subunit joining of the 60S to the 40S and correct ribosome positioning (43,44). Furthermore, by studying mice with a short tail phenotype, rpL38 was found to be required for 80S formation on Homeobox mRNAs and thus correct tissue patterning during development (45). RpL40 is localized on the surface of the ribosome, and its amino and carboxy termini are unblocked, providing potential sites to interact with mRNAs or proteins ( Fig.…”

Ribosome stoichiometry: from form to function.

“…For example, we have demonstrated differences in RP stoichiometry in ribosomes purified from wildtype cells [23], though the functional specificity is implied by a correlation, not shown by direct measurement. Even the prominent example suggesting ribosome specialization, RPL38 regulating HOX genes [39,42], falls short of direct proof since (i) its exclusive specificity to 3 HOX is implied and not directly measured and (ii) the existence of ribosomes lacking RPL38 in wildtype cells is assumed, not measured. However, more recent data from the Barna lab identified distinct mRNA subsets exhibiting enriched or diminished ribosome association with subsets of ribosomes enriched for RPL10a [24], and Ferretti & colleagues demonstrated a specific role for RPS26-containing ribosomes [37].…”

“…Horos et al, 2012 [38] reported that a single RP, S19, affects the ribosomal density along hundreds of mRNAs essential for the differentiation of murine and human erythroblasts. Other studies also report that RP perturbations can affect the translation of hundreds of genes organized in coherent functional groups [24,39]. RPs are routinely dysregulated in the context of cancer [36,40], and adjusted throughout cell growth and metabolic cycles [41].…”

“…Barna and colleagues have suggested that RPL38, affects specifically the synthesis of only three proteins. However, the authors did not measure genome-wide translation so the possibility that the synthesis of other proteins is altered as well cannot be excluded [39,42]. Loss of RPS25 also resulted in inhibition of viral IRES-based translation, though not cap-dependent cellular translation [43].…”