Adriamycin induces notochord hypertrophy with conservation of sonic hedgehog expression in abnormal ectopic notochord in the adriamycin rat model

Mortell, Alan; O’Donnell, Anne-Marie; Giles, Sally; Bannigan, John; Puri, Prem

doi:10.1016/j.jpedsurg.2004.02.040

Cited by 13 publications

(17 citation statements)

References 20 publications

(12 reference statements)

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“…Studies using Adriamycin or ENU rat models of ARMs have suggested that the notochord abnormalities induced by these teratogens underlie the anorectal defects seen in treated ani- mals (Arsic et al, 2004, Gillick et al, 2003, Mortell et al, 2004, Qi et al, 2003. It has also been suggested that the ectopic notochord would lead to a relative increase in Shh signalling, which may be responsible for the ARMs seen in these models (Arsic et al, 2004, Mortell et al, 2004.…”

Section: High Levels Of Hh Activity Are Necessary For Correct Anorectmentioning

confidence: 99%

“…It has also been suggested that the ectopic notochord would lead to a relative increase in Shh signalling, which may be responsible for the ARMs seen in these models (Arsic et al, 2004, Mortell et al, 2004. Since Hh proteins can act as morphogens, eliciting differing responses in target cells as a function of their concentration (Ericson et al, 1997, Ingham and Fietz, 1995, Struhl et al, 1997 proposals that axial midline derived Hh activity is required for anorectal development would imply that the target tissues respond to a low dose of Hhs, as the urorectal area is some distance from the notochord.…”

Section: High Levels Of Hh Activity Are Necessary For Correct Anorectmentioning

confidence: 99%

“…Prenatal exposure of foetal rats to the drug Adriamycin induces various malformations similar to those seen in the VACTERL association, providing a model that has been used extensively to investigate the various anomalies including the consistently occurring ARMs (Gillick et al, 2003, Kolker et al, 2000, Millar et al, 2001, Mortell et al, 2004. Several studies have shown that the expression of Shh is altered in the Adriamycin treated rats (Arsic et al, 2004, Arsic et al, 2003, Spilde et al, 2003.…”

Section: Introductionmentioning

confidence: 98%

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Hedgehog signalling is required for cloacal development in the zebrafish embryo

Parkin¹,

Allen²,

Ingham³

2009

Int. J. Dev. Biol.

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The Hedgehog (Hh) family of signalling molecules is essential for a wide range of developmental processes. Mammalian studies have implicated the Hedgehog pathway in the aetiology of anorectal malformations (ARMs), relatively common congenital anomalies caused by failures in the development of the cloaca. In this study we demonstrate that Hh signalling is absolutely required for the formation of the zebrafish cloaca and that the severity of the posterior gut abnormalities induced by a reduction in Hh activity is dependent on the levels of Hh signal transduction. The complete loss of all Hh activity results in the most severe defects and the critical period for Hh activity is between 34 and 74 hours post fertilisation. Using a range of mutant genotypes that cause notochord and floorplate abnormalities, we show that the source of the Hh signals required for posterior gut formation is the endoderm and not the notochord, as previously postulated in mammalian models of ARMs. We show that Adriamycin, a drug known to cause ARMs in rat, but not chick embryos, has no effect on the development of the zebrafish gastrointestinal tract. These studies establish the zebrafish as a model for ARMs, and for the elucidation of other pathways involved in hindgut developmental processes.

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Section: High Levels Of Hh Activity Are Necessary For Correct Anorectmentioning

confidence: 99%

Section: High Levels Of Hh Activity Are Necessary For Correct Anorectmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Hedgehog signalling is required for cloacal development in the zebrafish embryo

Parkin¹,

Allen²,

Ingham³

2009

Int. J. Dev. Biol.

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“…In contrast, Adriamycin-treated embryos demonstrated a low level of Shh expression throughout the same time period. In a quantitative morphological study of the notochord, Mortell et al [23] demonstrated a significant increase in the relative notochord volume of Adriamycin-treated embryos compared to controls. Immunohistochemically, the accessory branches of notochord, which contributed to this increased volume, expressed Shh similar to control notochord.…”

Section: Animal Models Of the Vater Associationmentioning

confidence: 99%

Animal models in pediatric surgery

2005

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“…In the neural crest, there was reduced auto-induction of Shh expression when the notochord was ectopically positioned closer [Goh et al, 1997]. The concentration of Shh received by the foregut in the ARM could arguably be higher due to either increased volume of notochord tissue or the proximity of the notochord branch to the foregut, and in response, the endodermal expression of Shh may decline [Mortell et al, 2004a]. Gli2 mRNA levels were lower in the fistula than in the oesophagus in the ARM, and the fistula, although Shh negative, was induced to branch by exogenous Shh in culture [Spilde et al, 2003a, c].…”

Section: Shh Pathwaymentioning

confidence: 99%

Adriamycin-Induced Models of VACTERL Association

et al. 2012

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Animal models are of great importance for medical research. They have enabled analysis of the aetiology and pathogenesis of complex congenital malformations and have also led to major advances in the surgical and therapeutic management of these conditions. Animal models allow us to comprehend the morphological and molecular basis of disease and consequently to discover novel approaches for both surgical and medical therapy. The anthracycline antibiotic adriamycin was incidentally found to have teratogenic effects on rats, producing a range of defects remarkably similar to the VACTERL association of congenital anomalies in humans, providing a reproducible animal model of this condition. VACTERL association is a spectrum of birth defects which includes vertebral, anal, cardiovascular, tracheo-oesophageal, renal and limb anomalies. In recent years, adriamycin rodent models of VACTERL have provided valuable insights into the pathogenesis of this complex association, particularly in relation to tracheo-oesophageal malformations. The adriamycin rat model and adriamycin mouse model are now well established in the investigation of the morphology of faulty organogenesis and the regulation of gene expression in tracheo-oesophageal anomalies.

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Adriamycin induces notochord hypertrophy with conservation of sonic hedgehog expression in abnormal ectopic notochord in the adriamycin rat model

Cited by 13 publications

References 20 publications

Hedgehog signalling is required for cloacal development in the zebrafish embryo

Hedgehog signalling is required for cloacal development in the zebrafish embryo

Animal models in pediatric surgery

Adriamycin-Induced Models of VACTERL Association

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