Drosophila as a model for the identification of genes causing adult human heart disease

Abstract

Drosophila melanogaster genetics provides the advantage of molecularly defined P-element insertions and deletions that span the entire genome. Although Drosophila has been extensively used as a model system to study heart development, it has not been used to dissect the genetics of adult human heart disease because of an inability to phenotype the adult fly heart in vivo. Here we report the development of a strategy to measure cardiac function in awake adult Drosophila that opens the field of Drosophila genetics to the study of human dilated cardiomyopathies. Through the application of optical coherence tomography, we accurately distinguish between normal and abnormal cardiac function based on measurements of internal cardiac chamber dimensions in vivo. Normal Drosophila have a fractional shortening of 87 ؎ 4%, whereas cardiomyopathic flies that contain a mutation in troponin I or tropomyosin show severe impairment of systolic function. To determine whether the fly can be used as a model system to recapitulate human dilated cardiomyopathy, we generated transgenic Drosophila with inducible cardiac expression of a mutant of human ␦-sarcoglycan (␦sg S151A ), which has previously been associated with familial dilated cardiomyopathy. Compared to transgenic flies overexpressing wild-type ␦sg, or the standard laboratory strain w 1118 , Drosophila expressing ␦sg S151A developed marked impairment of systolic function and significantly enlarged cardiac chambers. These data illustrate the utility of Drosophila as a model system to study dilated cardiomyopathy and the applicability of the vast genetic resources available in Drosophila to systematically study the genetic mechanisms responsible for human cardiac disease.optical coherence tomography ͉ cardiomyopathy

Downstream of Homeotic Genes: In the Heart of Hox function

“…55 Finally, the genetic programs preceding to Drosophila cardiogenesis have been extensively characterized, 63,64 as well as the consequences of their inactivation upon cell fate and differentiation and, more recently, on organ physiology. 55,[65][66][67] These studies have provided multiple useful criteria to appreciate the consequences of gene inactivation or misexpression. This extensive read out, combined with the strength of the genetic tools available, constitutes a real power in the analysis of what Hox genes are precisely doing and when their functions are required.…”

Pathologies et vieillissement cardiaque

“…La mise au point cette dernière décennie de différentes techniques permettant d'évaluer la fonction cardiaque [10] a permis de valider la drosophile comme modèle des maladies cardiaques. Une méthode non invasive, la tomographie par cohérence optique, utilise une technique d'échographie sans contact afin de visualiser les contractions du coeur au travers de la cuticule abdominale [11]. Sa résolution est particulièrement adaptée à la mesure de la fréquence cardiaque et à la variation de la taille du coeur que l'on observe, notamment dans des modèles de drosophile de cardiomyopathies dilatées [11].…”

“…Une méthode non invasive, la tomographie par cohérence optique, utilise une technique d'échographie sans contact afin de visualiser les contractions du coeur au travers de la cuticule abdominale [11]. Sa résolution est particulièrement adaptée à la mesure de la fréquence cardiaque et à la variation de la taille du coeur que l'on observe, notamment dans des modèles de drosophile de cardiomyopathies dilatées [11]. Pour l'analyse du rythme et de la contractilité, une meilleure précision est obtenue avec des préparations semi-intactes dans lesquelles le coeur de la mouche nettoyé du corps gras, baigne dans une solution physiologique oxygénée.…”

Big, bad hearts: From flies to man

“…Orthologous genes direct cardiac cell fate decisions (e.g., nkx 2.5) and the generation of the contractile sarcomeres (9, 10). It is reasonable to presume that important molecular pathways related to contractility are shared and, as Wolf et al (4) demonstrate, that mutations of sarcomeric proteins do lead to diminished contractile function and cardiac enlargement.…”

“…In a recent issue of PNAS, Wolf et al (4) chose heart contractility as the physiological target. They monitored and quantitated how well the beating heart of an adult fly empties on each beat and did so noninvasively, using optical coherence tomography (OCT), a technique that creates an image of the sample by analyzing its interference pattern of a broadband light source emission.…”