The bHLH Transcription Factor Hand Regulates the Expression of Genes Critical to Heart and Muscle Function in Drosophila melanogaster

Abstract

Hand proteins belong to the highly conserved family of basic Helix-Loop-Helix transcription factors and are critical to distinct developmental processes, including cardiogenesis and neurogenesis in vertebrates. In Drosophila melanogaster a single orthologous hand gene is expressed with absence of the respective protein causing semilethality during early larval instars. Surviving adult animals suffer from shortened lifespan associated with a disorganized myofibrillar structure being apparent in the dorsal vessel, the wing hearts and in midgut tissue. Based on these data, the major biological significance of Hand seems to be related to muscle development, maintenance or function; however, up to now the physiological basis for Hand functionality remains elusive. Thus, the identification of genes whose expression is, directly or indirectly, regulated by Hand has considerable relevance with respect to understanding its biological functionality in flies and vertebrates. Beneficially, hand mutants are viable and exhibit affected tissues, which renders Drosophila an ideal model to investigate up- or downregulated target genes by a comparative microarray approach focusing on the respective tissues from mutant specimens. Our present work reveals for the first time that Drosophila Hand regulates the expression of numerous genes of diverse physiological relevancy, including distinct factors required for proper muscle development and function such as Zasp52 or Msp-300. These results relate Hand activity to muscle integrity and functionality and may thus be highly beneficial to the evaluation of corresponding hand phenotypes.

The Fruit Fly, Drosophila melanogaster: Modeling of Human Diseases (Part II)

“…Tinman is a homeobox transcription factor discovered in Drosophila and it is a master gene of cardiac development conserved in higher organisms [57,58]. In addition, pannier and hand, which play crucial roles for heart specification as well as neuromancer, have counterparts in humans [59][60][61]. Moreover, these signaling pathways are required for some adult function both in Drosophila and in mammals suggesting that they have a conserved physiology [62].…”

On the Morphology of the Drosophila Heart

“…All cardiomyocytes express characteristic muscle-specific sarcomere proteins such as Myosin, Zasp52 ( Figure 2 ), or others, along with the transcription factors that potentially activate the expression of such proteins. Transcriptome [ 40 , 41 , 42 , 43 ] and proteomic [ 44 ] analyses based on dissected heart tissue or isolated cardiac cells have been successfully used to identify the repertoire of genes expressed in the Drosophila heart. These analyses led to the first insights into how cardiac genes are regulated on a global level.…”

Dissecting the Role of the Extracellular Matrix in Heart Disease: Lessons from the Drosophila Genetic Model

“…Drosophila possesses a single Mef2 gene, Dmef2, which is expressed in myocardial precursors [ 60 , 61 ]. Its Hand gene, encoding a basic helix-loop-helix (bHLH) protein expressed in cardiac precursors, has orthologues in vertebrates, including chicks and mice [ 51 , 62 , 63 , 64 ]. Vertebrate COUP-TF/NR2F is homologous with Drosophila ’s Seven-up (Svp) [ 65 ], and Islet-1 (Isl1), which is involved in cardiac precursor specification, has a Drosophila counterpart in Tailup (Tup) [ 66 ].…”