kidney-regeneration-in-adult-zebrafish-by-gentamicin-induced-injury

Kidney Regeneration in Adult Zebrafish by Gentamicin Induced Injury

The kidney is essential for fluid homeostasis, blood pressure regulation and filtration of waste from the body. The fundamental unit of kidney function is ...

Massachusetts General Hospital

Ventricular septal defects are common in human infants, but the genetic programs that control ventricular septation are poorly understood. Here we report that mice with a targeted disruption of the cardiovascular basic helix-loop-helix factor (CHF)1Hey2 gene show isolated ventricular septal defects. These defects result primarily in failure to thrive. Mice often succumbed within the first 3 wk after birth and showed pulmonary and liver congestion. The penetrance of this phenotype varied, depending on genetic background, suggesting the presence of modifier genes. Expression patterns of other cardiac-specific genes were not affected. Of the few animals on a mixed genetic background that survived to adulthood, most developed a cardiomyopathy but did not have ventricular septal defects. Our results indicate that CHF1 plays an important role in regulation of ventricular septation in mammalian heart development and is important for normal myocardial contractility. These mice provide a useful model for the study of the ontogeny and natural history of ventricular septal defects and cardiomyopathy.

Ventricular septal defect and cardiomyopathy in mice lacking the transcription factor CHF1/Hey2.

To determine the role of the cardiovascular-restricted, hairy-related bHLH transcription factor, CHF1/Hey2, in the biological response to vascular injury.

Transcription factor CHF1/Hey2 regulates neointimal formation in vivo and vascular smooth muscle proliferation and migration in vitro.

CHF1/Hey2 null mice generated in different laboratories have discrepant cardiovascular phenotypes. To determine the effect of genetic background on phenotype, we backcrossed our knockout strain more than eight generations to the inbred strains BALB/c and C57BL/6. Knockout mice on these backgrounds showed disparate phenotypes. Mice on both backgrounds demonstrated ventricular septal defects (VSDs), tricuspid stenosis and mitral valve thickening, but at varying frequencies, suggesting a general defect in endocardial cushion remodeling. Additional defects seen exclusively on the C57BL/6 background included biventricular wall thinning and left ventricular enlargement, implying a more severe myocardial defect than previously observed. In addition, aortas and pulmonary arteries from these null mice had thinner walls. Intercrossing of the CHF1/Hey2 null mice on a C57BL/6 background with a C57BL/6 MLC2v-CHF1/Hey2 transgenic line overexpressing CHF1/Hey2 in the atrial and ventricular myocardium also rescued the VSD and myocardial phenotypes, but did not affect vascular wall thickness. Our results indicate that CHF1/Hey2 provides an important myocardial signal to the endocardial cushion for proper septation and valve formation and also plays an important role in maturation of the myocardium and vasculature.

The spectrum of cardiovascular anomalies in CHF1/Hey2 deficient mice reveals roles in endocardial cushion, myocardial and vascular maturation.

Formation of kidney tissue requires the generation of kidney precursor cells and their subsequent differentiation into nephrons, the functional filtration unit of the kidney. Here we report that the gene odd-skipped related 1 (Odd1) plays an important role in both these processes. Odd1 is the earliest known marker of the intermediate mesoderm, the precursor to all kidney tissue. It is localized to mesenchymal precursors within the mesonephric and metanephric kidney and is subsequently downregulated upon tubule differentiation. Mice lacking Odd1 do not form metanephric mesenchyme, and do not express several other factors required for metanephric kidney formation, including Eya1, Six2, Pax2, Sall1 and Gdnf. In transient ectopic expression experiments in the chick embryo, Odd1 can promote expression of the mesonephric precursor markers Pax2 and Lim1. Finally, persistent expression of Odd1 in chick mesonephric precursor cells inhibits differentiation of these precursors into kidney tubules. These data indicate that Odd1 plays an important role in establishing kidney precursor cells, and in regulating their differentiation into kidney tubular tissue.

Odd-skipped related 1 is required for development of the metanephric kidney and regulates formation and differentiation of kidney precursor cells.

In the avian embryo, endothelial cells originate from several sources, including the lateral plate and somite mesoderm. In this study, we show that Gata transcription factors are expressed in the lateral plate and in vasculogenic regions of the avian somite and are able to promote a vascular endothelial fate when ectopically expressed in somite precursors. A fusion of GATA4 to the transcriptional activator VP16 promoted endothelium formation, indicating that GATA transcription factors promote vasculogenesis via activation of downstream targets, while a fusion of GATA4 to the transcriptional repressor engrailed repressed expression of Vascular Endothelial Growth Factor Receptor 2, a marker of endothelial precursors. These findings indicate a role for GATA transcription factors in the differentiation of the endothelium.

Promotion of avian endothelial cell differentiation by GATA transcription factors.

odd-skipped related 2 (osr2) encodes a vertebrate ortholog of the Drosophila odd-skipped zinc-finger transcription factor. Osr2 in mouse is required for proper palate, eyelid, and bone development. Zebrafish knock-down experiments have also suggested a role for osr2, along with its paralog osr1, in early pectoral fin specification and pronephric development.

Article	Year
Ventricular septal defect and cardiomyopathy in mice lacking the transcription factor CHF1/Hey2. Proceedings of the National Academy of Sciences of the United States of America\| PubMed ID: 12454287	2002
Transcription factor CHF1/Hey2 regulates neointimal formation in vivo and vascular smooth muscle proliferation and migration in vitro. Arteriosclerosis, thrombosis, and vascular biology\| PubMed ID: 15345511	2004
The spectrum of cardiovascular anomalies in CHF1/Hey2 deficient mice reveals roles in endocardial cushion, myocardial and vascular maturation. Journal of molecular and cellular cardiology\| PubMed ID: 16242143	2006
Odd-skipped related 1 is required for development of the metanephric kidney and regulates formation and differentiation of kidney precursor cells. Development (Cambridge, England)\| PubMed ID: 16790474	2006
Promotion of avian endothelial cell differentiation by GATA transcription factors. Developmental biology\| PubMed ID: 21354132	2011
odd-skipped related 2 is required for fin chondrogenesis in zebrafish. Developmental dynamics : an official publication of the American Association of Anatomists\| PubMed ID: 23913342	2013

Caramai N. Kamei

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