Abstract
liver-enriched gene 1 (leg1) is a liver-enriched gene in zebrafish and encodes a novel protein. Our preliminary data suggested that Leg1 is probably involved in early liver development. However, no detailed characterization of Leg1 has been reported thus far. We undertook both bioinformatic and experimental approaches to study leg1 gene structure and its role in early liver development. We found that Leg1 identifies a new conserved protein superfamily featured by the presence of domain of unknown function 781 (DUF781). There are two copies of leg1 in zebrafish, namely leg1a and leg1b. Both leg1a and leg1b are expressed in the larvae and adult liver with leg1a being the predominant form. Knockdown of Leg1a or Leg1b by their respective morpholinos specifically targeting their 5′-UTR each resulted in a small liver phenotype, demonstrating that both Leg1a and Leg1b are important for early liver development. Meanwhile, we found that injection of leg1-ATGMO, a morpholino which can simultaneously block the translation of Leg1a and Leg1b, caused not only a small liver phenotype but hypoplastic exocrine pancreas and intestinal tube as well. Further examination of leg1-ATGMO morphants with early endoderm markers and early hepatic markers revealed that although depletion of total Leg1 does not alter the hepatic and pancreatic fate of the endoderm cells, it leads to cell cycle arrest that results in growth retardation of liver, exocrine pancreas and intestine. Finally, we proved that Leg1 is a secretory protein. This intrigued us to propose that Leg1 might act as a novel secreted regulator that is essential for liver and other digestive organ development in zebrafish.
Highlights
Liver expresses vast varieties of genes, including liver-specific and/or –enriched genes, to encode different proteins necessary for executing its diverse functions [1,2,3]
This work is important since continuous expression of this set of live-enriched genes from the fetal to adult stages suggest their essential roles in both early liver development and stem cell function and/or the status maintainence in an adult liver [13]
We found that all four markers are expressed in the leg1-MOATG morphant embryos in a similar pattern as that observed in the wild type (WT) control (Fig. 6B)
Summary
Liver expresses vast varieties of genes, including liver-specific and/or –enriched genes, to encode different proteins necessary for executing its diverse functions [1,2,3]. Extensive genetic studies have demonstrated that, in addition to their roles in controlling the expression of metabolic genes, all HNF proteins are essential for liver organogenesis. The process of liver organogenesis is governed by a network formed by HNF factors, GATA factors, and morphogens including FGF, BMP and Wnt2 [7,8,9] This genetic network coordinates expression and functions of many genes to guide the liver to develop into the right size and shape at the right time and place. This work is important since continuous expression of this set of live-enriched genes from the fetal to adult stages suggest their essential roles in both early liver development and stem cell function and/or the status maintainence in an adult liver [13]. These results suggest that Leg might function as a novel secreted regulator for the liver development
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