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Dose-dependent Smad1, Smad5 and Smad8 signaling in the early mouse embryo.

ABSTRACT: Three closely related mammalian R-Smads, namely Smad1, Smad5 and Smad8, are activated by BMP receptors. Here we have taken a genetic approach to further dissect their possibly unique and/or shared roles during early mouse development. A Smad8.LacZ reporter allele was created to visualize Smad8 expression domains. Smad8 is initially expressed only in the visceral yolk sac (VYS) endoderm and shows a highly restricted pattern of expression in the embryo proper at later stages. In addition, Smad8 conditional and null alleles were engineered. All alleles clearly demonstrate that adult Smad8 homozygous mutants are viable and fertile. To elucidate gene dosage effects, we manipulated expression ratios of the three BMP R-Smads. Smad8 homozygotes also lacking one copy of Smad1 or Smad5 did not exhibit overt phenotypes, and the tissue disturbances seen in Smad1 or Smad5 null embryos were not exacerbated in the absence of Smad8. However, we discovered a profound genetic interaction between Smad1 and Smad5. Thus, as for Smad1 and Smad5 mutant embryos, Smad1+/-:Smad5+/- double heterozygotes die by E10.5 and display defects in allantois morphogenesis, cardiac looping and primordial germ cell (PGC) specification. These experiments demonstrate for the first time that Smad1 and Smad5 function cooperatively to govern BMP target gene expression in the early mammalian embryo.

SUBMITTER: Arnold SJ

PROVIDER: S-EPMC7116376 | biostudies-literature | 2006 Aug

REPOSITORIES: biostudies-literature

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Dose-dependent Smad1, Smad5 and Smad8 signaling in the early mouse embryo.

Arnold Sebastian J SJ Maretto Silvia S Islam Ayesha A Bikoff Elizabeth K EK Robertson Elizabeth J EJ

Developmental biology 20060801 1

Three closely related mammalian R-Smads, namely Smad1, Smad5 and Smad8, are activated by BMP receptors. Here we have taken a genetic approach to further dissect their possibly unique and/or shared roles during early mouse development. A Smad8.LacZ reporter allele was created to visualize Smad8 expression domains. Smad8 is initially expressed only in the visceral yolk sac (VYS) endoderm and shows a highly restricted pattern of expression in the embryo proper at later stages. In addition, Smad8 co ...[more]

PMID: 16765933

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Project description:A failure of iron to appropriately regulate liver hepcidin production is central to the pathogenesis of hereditary hemochromatosis. SMAD1/5 transcription factors, activated by bone morphogenetic protein (BMP) signaling, are major regulators of hepcidin production in response to iron; however, the role of SMAD8 and the contribution of SMADs to hepcidin production by other systemic cues remain uncertain. Here, we generated hepatocyte Smad8 single (Smad8fl/fl ;Alb-Cre+ ), Smad1/5/8 triple (Smad158;Alb-Cre+ ), and littermate Smad1/5 double (Smad15;Alb-Cre+ ) knockout mice to investigate the role of SMAD8 in hepcidin and iron homeostasis regulation and liver injury. We found that Smad8;Alb-Cre+ mice exhibited no iron phenotype, whereas Smad158;Alb-Cre+ mice had greater iron overload than Smad15;Alb-Cre+ mice. In contrast to the sexual dimorphism reported for wild-type mice and other hemochromatosis models, hepcidin deficiency and extrahepatic iron loading were similarly severe in Smad15;Alb-Cre+ and Smad158;Alb-Cre+ female compared with male mice. Moreover, epidermal growth factor (EGF) failed to suppress hepcidin in Smad15;Alb-Cre+ hepatocytes. Conversely, hepcidin was still increased by lipopolysaccharide in Smad158;Alb-Cre+ mice, although lower basal hepcidin resulted in lower maximal hepcidin. Finally, unlike most mouse hemochromatosis models, Smad158;Alb-Cre+ developed liver injury and fibrosis at 8 weeks. Liver injury and fibrosis were prevented in Smad158;Alb-Cre+ mice by a low-iron diet and were minimal in iron-loaded Cre- mice. Conclusion: Hepatocyte Smad1/5/8 knockout mice are a model of hemochromatosis that encompasses liver injury and fibrosis seen in human disease. These mice reveal the redundant but critical role of SMAD8 in hepcidin and iron homeostasis regulation, establish a requirement for SMAD1/5/8 in hepcidin regulation by testosterone and EGF but not inflammation, and suggest a pathogenic role for both iron loading and SMAD1/5/8 deficiency in liver injury and fibrosis.

Dataset Information

Dose-dependent Smad1, Smad5 and Smad8 signaling in the early mouse embryo.

Publications

Dose-dependent Smad1, Smad5 and Smad8 signaling in the early mouse embryo.

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