Alpha2 Macroglobulin-Like Is Essential for Liver Development in Zebrafish

Hong, Sung-Kook; Dawid, Igor B.

doi:10.1371/journal.pone.0003736

Cited by 18 publications

(11 citation statements)

References 33 publications

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“…A2ml1 is predominantly expressed in the liver during embryonic development and morpholinomediated knockdown of a2ml1 has previously been shown to induce defective liver development. 17 We introduced human A2ML1 mutations (p.R802H, p.R802L and p.S592L, human numbering for clarity, see Table 1) in zebrafish A2ml1, C-terminally fused with GFP, allowing to monitor (mutant) A2ml1 expression in tissue culture cells and during development (Supplementary Figures 3 and 4). Expression of most mutant NS-associated genes in tissue culture cells augments activation of the RAS/MAPK pathway, measurable by excessive ERK/MAPK phosphorylation in cycling cells.…”

Section: A2ml1 Mutations In a Noonan Syndrome-like Disorder Lelm Vissmentioning

confidence: 99%

Heterozygous germline mutations in A2ML1 are associated with a disorder clinically related to Noonan syndrome

et al. 2014

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Noonan syndrome (NS) is a developmental disorder characterized by short stature, facial dysmorphisms and congenital heart defects. To date, all mutations known to cause NS are dominant, activating mutations in signal transducers of the RAS/ mitogen-activated protein kinase (MAPK) pathway. In 25% of cases, however, the genetic cause of NS remains elusive, suggesting that factors other than those involved in the canonical RAS/MAPK pathway may also have a role. Here, we used family-based whole exome sequencing of a case-parent trio and identified a de novo mutation, p.(Arg802His), in A2ML1, which encodes the secreted protease inhibitor a-2-macroglobulin (A2M)-like-1. Subsequent resequencing of A2ML1 in 155 cases with a clinical diagnosis of NS led to the identification of additional mutations in two families, p.(Arg802Leu) and p.(Arg592Leu). Functional characterization of these human A2ML1 mutations in zebrafish showed NS-like developmental defects, including a broad head, blunted face and cardiac malformations. Using the crystal structure of A2M, which is highly homologous to A2ML1, we identified the intramolecular interaction partner of p.Arg802. Mutation of this residue, p.Glu906, induced similar developmental defects in zebrafish, strengthening our conclusion that mutations in A2ML1 cause a disorder clinically related to NS. This is the first report of the involvement of an extracellular factor in a disorder clinically related to RASopathies, providing potential new leads for better understanding of the molecular basis of this family of developmental diseases.

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Section: A2ml1 Mutations In a Noonan Syndrome-like Disorder Lelm Vissmentioning

confidence: 99%

Heterozygous germline mutations in A2ML1 are associated with a disorder clinically related to Noonan syndrome

et al. 2014

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“…Matrix metalloproteinase activity promotes hepatocyte proliferation upstream of tumor necrosis factor (TNF) signaling, as demonstrated by MO-mediated knockdown of mmp23b (149). Liver growth is also impaired in α 2-macroglobulin-like deficient embryos (78), and is arrested at 72 hpf by mutation of nil per os (npo) , an RNA binding protein (121). Endothelial cells and blood circulation are required for liver growth, as previously mentioned (97).…”

Section: Liver Development In Zebrafishmentioning

confidence: 99%

Zebrafish Models of Human Liver Development and Disease

Wilkins

Pack

2013

Comprehensive Physiology

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The liver performs a large number of essential synthetic and regulatory functions that are acquired during fetal development and persist throughout life. Their disruption underlies a diverse group of heritable and acquired diseases that affect both pediatric and adult patients. Although experimental analyses used to study liver development and disease are typically performed in cell culture models or rodents, the zebrafish is increasingly used to complement discoveries made in these systems. Forward and reverse genetic analyses over the past two decades have shown that the molecular program for liver development is largely conserved between zebrafish and mammals, and that the zebrafish can be used to model heritable human liver disorders. Recent work has demonstrated that zebrafish can also be used to study the mechanistic basis of acquired liver diseases. Here, we provide a comprehensive summary of how the zebrafish has contributed to our understanding of human liver development and disease.

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“…According to Armstrong (2006) [39], the diversity of the bait region sequences in a 2 Ms make them ideal scavengers for the diverse array of protease produced by the broad spectrum of pathogens that might attack during the lifetime of any given animal. Fourth, like most vertebrate (zebrafish, chicken, carp, frog and mouse) a 2 Ms [40,8,41,12,34], Bja 2 M also lacks the KPTVK motif in the receptor-binding region, which is present in some mammalian (including humans) a 2 Ms [42]. This suggests that the KPTVK motif in the receptor-binding region may be a novelty to mammalian a 2 Ms during chordate evolution.…”

Section: Discussionmentioning

confidence: 98%