Abstract
Ribosome biogenesis is a fundamental activity in cells. Ribosomal dysfunction underlies a category of diseases called ribosomopathies in humans. The symptomatic characteristics of ribosomopathies often include abnormalities in craniofacial skeletons, digestive organs, and hematopoiesis. Consistently, disruptions of ribosome biogenesis in animals are deleterious to embryonic development with hypoplasia of digestive organs and/or impaired hematopoiesis. In this study, ltv1, a gene involved in the small ribosomal subunit assembly, was knocked out in zebrafish by clustered regularly interspaced short palindromic repeats (CRISPRs)/CRISPR associated protein 9 (Cas9) technology. The recessive lethal mutation resulted in disrupted ribosome biogenesis, and ltv1Δ14/Δ14 embryos displayed hypoplastic craniofacial cartilage, digestive organs, and hematopoiesis. In addition, we showed that the impaired cell proliferation, instead of apoptosis, led to the defects in exocrine pancreas and hematopoietic stem and progenitor cells (HSPCs) in ltv1Δ14/Δ14 embryos. It was reported that loss of function of genes associated with ribosome biogenesis often caused phenotypes in a P53-dependent manner. In ltv1Δ14/Δ14 embryos, both P53 protein level and the expression of p53 target genes, Δ113p53 and p21, were upregulated. However, knockdown of p53 failed to rescue the phenotypes in ltv1Δ14/Δ14 larvae. Taken together, our data demonstrate that LTV1 ribosome biogenesis factor (Ltv1) plays an essential role in digestive organs and hematopoiesis development in zebrafish in a P53-independent manner.
Highlights
The ribosome is a fundamental macromolecular machine, found within all living cells, that synthesizes proteins according to mRNA sequences
RNA whole mount in situ hybridization (WISH) showed that ltv1 transcripts were almost absent in ltv1∆14/∆14 mutant at 3 days post fertilization, indicating that the knockout of ltv1 was successful (Figure 1C)
LTV1 ribosome biogenesis factor (Ltv1) was demonstrated functionally conserved in zebrafish as illustrated by disrupted 18S ribosomal RNAs (rRNAs) processing in the ltv1 mutants
Summary
The ribosome is a fundamental macromolecular machine, found within all living cells, that synthesizes proteins according to mRNA sequences. Ribosome biogenesis is a very intricate process in cells (Warner, 2001). In addition to the four ribosomal RNAs (rRNAs) and 82 core ribosomal proteins, which are the components of the 80S ribosome, over 200 non-ribosomal proteins are involved in ribosome biogenesis. This precisely controlled process is inextricably associated with many fundamental cellular activities, such as growth and division (Panse and Johnson, 2010). Disruption of ribosome biogenesis leads to a
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