The BMP Antagonist Follistatin-Like 1 Is Required for Skeletal and Lung Organogenesis

Sylva, Marc; Li, Vivian; Buffing, Anita A. A.; Es, Johan H. van; Born, Marise Ph.; Velden, Saskia van der; Gunst, Quinn D.; Koolstra, J.H.; Moorman, Antoon F.M.; Clevers, Hans; Hoff, Maurice J.B. van den

doi:10.1371/journal.pone.0022616

Cited by 94 publications

(109 citation statements)

References 47 publications

(54 reference statements)

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“…To generate cardiac-specific Fstl1-deficient (cFstl1-KO) mice, mice with loxP sites flanking the exon 1 of the Fstl1 gene (Fstl1 flox/flox ) 16,59 were crossed with mice overexpressing Cre recombinase under the control of the a-myosin heavy chain promoter (a2myosin heavy chain-Cre) (The Jackson Laboratory). Both cFstl1-KO and control mice (8-11 weeks old) were assigned to two groups with or without subtotal renal ablation.…”

Section: Animal and Surgical Proceduresmentioning

confidence: 99%

Cardiac Myocyte-Derived Follistatin-Like 1 Prevents Renal Injury in a Subtotal Nephrectomy Model

Hayakawa¹,

Ohashi

Shibata³

et al. 2015

Journal of the American Society of Nephrology

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Heart disease contributes to the progression of CKD. Heart tissue produces a number of secreted proteins, also known as cardiokines, which participate in intercellular and intertissue communication. We recently reported that follistatin-like 1 (Fstl1) functions as a cardiokine with cardioprotective properties. Here, we investigated the role of cardiac Fstl1 in renal injury after subtotal nephrectomy. Cardiac-specific Fstl1-deficient (cFstl1-KO) mice and wild-type mice were subjected to subtotal (5/6) nephrectomy. cFstl1-KO mice showed exacerbation of urinary albumin excretion, glomerular hypertrophy, and tubulointerstitial fibrosis after subtotal renal ablation compared with wild-type mice. cFstl1-KO mice also exhibited increased mRNA levels of proinflammatory cytokines, including TNF-a and IL-6, NADPH oxidase components, and fibrotic mediators, in the remnant kidney. Conversely, systemic administration of adenoviral vectors expressing Fstl1 (Ad-Fstl1) to wild-type mice with subtotal nephrectomy led to amelioration of albuminuria, glomerular hypertrophy, and tubulointerstitial fibrosis, accompanied by reduced expression of proinflammatory mediators, NADPH oxidase components, and fibrotic markers in the remnant kidney. In cultured human mesangial cells, treatment with recombinant FSTL1 attenuated TNF-a-stimulated expression of proinflammatory cytokines. Treatment of mesangial cells with FSTL1 augmented the phosphorylation of AMP-activated protein kinase (AMPK), and inhibition of AMPK activation abrogated the anti-inflammatory effects of FSTL1. These data suggest that Fstl1 functions in cardiorenal communication and that the lack of Fstl1 production by myocytes promotes glomerular and tubulointerstitial damage in the kidney.

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Section: Animal and Surgical Proceduresmentioning

confidence: 99%

Cardiac Myocyte-Derived Follistatin-Like 1 Prevents Renal Injury in a Subtotal Nephrectomy Model

Hayakawa¹,

Ohashi

Shibata³

et al. 2015

Journal of the American Society of Nephrology

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“…Fstl1 is expressed in the mesenchyme surrounding the airways like Hoxa5 (49). Sequence analysis of the mouse Fstl1 gene with the Transcription Element Search System (TESS) software revealed five HOX binding sites into a 2.1-kb region located between positions Ϫ5.0 and Ϫ2.9 kb upstream the Fstl1 transcription start site (Fig.…”

Section: Expression Of Hox5 Paralog Genes In the Developing Lungmentioning

confidence: 99%

Partial functional redundancy betweenHoxa5andHoxb5paralog genes during lung morphogenesis

Boucherat

Montaron

Bérubé-Simard

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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Hox genes encode transcription factors governing complex developmental processes in several organs. A subset of Hox genes are expressed in the developing lung. Except for Hoxa5, the lack of overt lung phenotype in single mutants suggests that Hox genes may not play a predominant role in lung ontogeny or that functional redundancy may mask anomalies. In the Hox5 paralog group, both Hoxa5 and Hoxb5 genes are expressed in the lung mesenchyme whereas Hoxa5 is also expressed in the tracheal mesenchyme. Herein, we generated Hoxa5;Hoxb5 compound mutant mice to evaluate the relative contribution of each gene to lung development. Hoxa5;Hoxb5 mutants carrying the four mutated alleles displayed an aggravated lung phenotype, resulting in the death of the mutant pups at birth. Characterization of the phenotype highlighted the role of Hoxb5 in lung formation, the latter being involved in branching morphogenesis, goblet cell specification, and postnatal air space structure, revealing partial functional redundancy with Hoxa5. However, the Hoxb5 lung phenotypes were less severe than those seen in Hoxa5 mutants, likely because of Hoxa5 compensation. New specific roles for Hoxa5 were also unveiled, demonstrating the extensive contribution of Hoxa5 to the developing respiratory system. The exclusive expression of Hoxa5 in the trachea and the phrenic motor column likely underlies the Hoxa5-specific trachea and diaphragm phenotypes. Altogether, our observations establish that the Hoxa5 and Hoxb5 paralog genes shared some functions during lung morphogenesis, Hoxa5 playing a predominant role.

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“…For example, multiple extracellular binding partners for the TGF-β family, such as decorin (1), follistatin (2,3), chordin and noggin (4), have been characterized as regulators of TGF-β signaling. Follistatin-like 1 (FSTL1) is also a TGF-β superfamily binding protein; it has recently been identified as a bone morphogenetic protein 4 (BMP4) antagonist controlling embryonic development in mouse (5)(6)(7)(8) and zebrafish models (9,10). In vivo, FSTL1 is expressed temporally and spatially and is generally associated with tissues undergoing remodeling, either during normal developmental processes or in response to injury.…”

Section: Introductionmentioning

confidence: 99%

Expression, characterization, and preliminary X-ray crystallographic analysis of recombinant murine Follistatin-like 1 expressed in Drosophila S2 cells

Xue

et al. 2013

Biosci Trends

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The BMP Antagonist Follistatin-Like 1 Is Required for Skeletal and Lung Organogenesis

Cited by 94 publications

References 47 publications

Cardiac Myocyte-Derived Follistatin-Like 1 Prevents Renal Injury in a Subtotal Nephrectomy Model

Cardiac Myocyte-Derived Follistatin-Like 1 Prevents Renal Injury in a Subtotal Nephrectomy Model

Partial functional redundancy betweenHoxa5andHoxb5paralog genes during lung morphogenesis

Expression, characterization, and preliminary X-ray crystallographic analysis of recombinant murine Follistatin-like 1 expressed in Drosophila S2 cells

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