Ddx46 Is Required for Multi-Lineage Differentiation of Hematopoietic Stem Cells in Zebrafish

Abstract

Balanced and precisely controlled processes between self-renewal and differentiation of hematopoietic stem cells (HSCs) into all blood lineages are critical for vertebrate definitive hematopoiesis. However, the molecular mechanisms underlying the maintenance and differentiation of HSCs have not been fully elucidated. Here, we show that zebrafish Ddx46, encoding a DEAD-box RNA helicase, is expressed in HSCs of the caudal hematopoietic tissue (CHT). The number of HSCs expressing the molecular markers cmyb or T-cell acute lymphocytic leukemia 1 (tal1) was markedly reduced in Ddx46 mutants. However, massive cell death of HSCs was not detected, and proliferation of HSCs was normal in the CHT of the mutants at 48 h postfertilization. We found that myelopoiesis occurred, but erythropoiesis and lymphopoiesis were suppressed, in Ddx46 mutants. Consistent with these results, the expression of spi1, encoding a regulator of myeloid development, was maintained, but the expression of gata1a, encoding a regulator of erythrocyte development, was downregulated in the mutants. Taken together, our results provide the first genetic evidence that zebrafish Ddx46 is required for the multilineage differentiation of HSCs during development, through the regulation of specific gene expressions.

Endangered Père David’s deer genome provides insights into population recovering

“…In this current study, the genomewide analysis revealed that 17 putative genes involved in spermatogenesis, embryogenesis, and innate immune were under positive selection; these genes encode for DDX46 , TAB1 , EIF2AK2 , AOAH , FLT3 , ZNF335, and IL9R (Figure ). For instance, DDX46 encodes a member of the DEAD box protein family, and some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division (Hirabayashi, Hozumi, Higashijima, & Kikuchi, ). TAB1 plays an important role in mammalian embryogenesis (Komatsu et al, ).…”

“…For instance, DDX46 encodes a member of the DEAD box protein family, and some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division (Hirabayashi, Hozumi, Higashijima, & Kikuchi, 2013). TAB1 plays an important role in mammalian embryogenesis (Komatsu et al, 2002).…”

Lentiviral DDX46 knockdown inhibits growth and induces apoptosis in human colorectal cancer cells

“…In vitro studies have shown that DDX46 plays an essential role in pre-mRNA splicing before or during prespliceosome assembly (Dalbadie-McFarland and Abelson, 1990;Ruby et al, 1993;Xu et al, 2004;Xu and Query, 2007;Kosowski et al, 2009). Additionally, in vivo zebrafish studies have shown that DDX46 is required for multi-lineage differentiation of hematopoietic stem cells (Hirabayashi et al, 2013) and the development of the digestive organs and brain (Hozumi et al, 2012). However, whether DDX46 is expressed and plays a role in cancer progression in humans has not been reported.…”

Spliceosomal component Sf3b1 is essential for hematopoietic differentiation in zebrafish

“…U2 snRNP is a large macromolecular complex made up of nearly 20 factors. Zebrafish mutants of three of these factors ( sf3a3 15 , ddx46/prp5 12 , and now sf3b1) have been characterized, and all display defects in the hematopoietic system. Mutants in sf3a3 have normal primitive erythropoiesis and myelopoiesis, but show defects in HSPC formation, while ddx46 mutants initiate HSPC induction normally, but have problems maintaining their stem cell pool.…”