Steroid-dependent modification of Hox function drives myocyte reprogramming in theDrosophilaheart

Abstract

In the Drosophila larval cardiac tube, aorta and heart differentiation are controlled by the Hox genes Ultrabithorax(Ubx) and abdominal A (abdA), respectively. There is evidence that the cardiac tube undergoes extensive morphological and functional changes during metamorphosis to form the adult organ, but both the origin of adult cardiac tube myocytes and the underlying genetic control have not been established. Using in vivo time-lapse analysis, we show that the adult fruit fly cardiac tube is formed during metamorphosis by the reprogramming of differentiated and already functional larval cardiomyocytes,without cell proliferation. We characterise the genetic control of the process, which is cell autonomously ensured by the modulation of Ubxexpression and AbdA activity. Larval aorta myocytes are remodelled to differentiate into the functional adult heart, in a process that requires the regulation of Ubx expression. Conversely, the shape, polarity,function and molecular characteristics of the surviving larval contractile heart myocytes are profoundly transformed as these cells are reprogrammed to form the adult terminal chamber. This process is mediated by the regulation of AbdA protein function, which is successively required within these persisting myocytes for the acquisition of both larval and adult differentiated states. Importantly, AbdA specificity is switched at metamorphosis to induce a novel genetic program that leads to differentiation of the terminal chamber. Finally, the steroid hormone ecdysone controls cardiac tube remodelling by impinging on both the regulation of Ubx expression and the modification of AbdA function. Our results shed light on the genetic control of one in vivo occurring remodelling process, which involves a steroid-dependent modification of Hox expression and function.

Pathologies et vieillissement cardiaque

“…La partie la plus caudale est éliminée par apoptose et, dans l'aorte postérieure, les cardiomyocytes larvaires engagent un nouveau programme de différenciation conduisant au coeur adulte [5]. Ces évè-nements morphogénétiques sont sous le contrôle de différentes voies .…”

“…Le coeur, localisé en position dorsale juste sous la cuticule abdominale de l'adulte, est maintenu par les muscles alaires qui le connectent à l'épiderme. le filament épais de myosine, les composants du filament fin (actine, tropomyosine, troponines) mais également le récepteur à la ryanodine (RyR), la pompe calcique dépendante de l'ATP du réticulum sarcoplasmique (SERCA), les canaux ioniques possiblement impliqués dans l'activité pacemaker comme Ih/HCN (hyperpolarization-activated cyclic nucleotide modulated cation non-selective channel) [5], sont tous exprimés par les cardiomyocytes. Au niveau cellulaire, les cardiomyocytes de la mouche, comme ceux des mammifères, présentent des invaginations de la membrane plasmique formant des tubules T [9].…”

Downstream of Homeotic Genes: In the Heart of Hox function

“…(G) Ih, Ndae1 and Ork1 are abdA targets as their expression is lost in abdA mutant embryos, while they are ectopically expressed in the aorta when abdA is ectopically expressed. 40,55,56 Given the similarity of the expression patterns of CaP60A, sei and CaBeta with Ih, Ndae1 and Ork1, they are likely to respond to abdA regulation in the same way. 40,44,55,56 It is highly probable that the other identified genes expressed in the 20 CMs of the heart behave in the same way (Fig.…”

“…56 The adult fruit fly cardiac tube is formed during metamorphosis 58,59 by reprogramming the differentiated larval CMs, and during this process there is no cell proliferation or adjunction of new cells. 56 The larval posterior aorta CMs (segments A1-A4) are remodeled to differentiate into the functional adult heart, which presents all the morphological (cell size, shape, polarity), functional (differentiated ostia, contractile Tin-CMs) and molecular (restricted expression of wg, Ih and Ndae1) characteristics of the larval heart (Fig. 2E).…”

“…At the same time, segments A6-A7 of the larval heart are eliminated by apoptosis, while segment A5 trans-differentiates to form a new structure specific to the adult named 'terminal chamber'. 56 During remodeling, Hox genes do not change their relative expression patterns. Interestingly, the genetic control of this process is cell-autonomously ensured by modulation of Ubx expression and of abdA activity.…”