RESUMEN
Circadian rhythms are regulated by a highly conserved transcriptional/translational feedback loop that maintains approximately 24-hr periodicity from cellular to organismal levels. Much research effort is being devoted to understanding how the outputs of the master clock affect peripheral oscillators, and in turn, numerous biological processes. Recent studies have revealed roles for circadian timing in the regulation of numerous cellular behaviours in support of complex tissue regeneration. One such role involves the interaction between the circadian clockwork and the cell cycle. The molecular mechanisms that control the cell cycle create a system of regulation that allows for high fidelity DNA synthesis, mitosis and apoptosis. In recent years, it has become clear that clock gene products are required for proper DNA synthesis and cell cycle progression, and conversely, elements of the cell cycle cascade feedback to influence molecular circadian timing mechanisms. It is through this crosstalk that the circadian system orchestrates stem cell proliferation, niche exit and control of the signalling pathways that govern differentiation and self-renewal. In this review, we discuss the evidence for circadian control of tissue homeostasis and repair and suggest new avenues for research.
Asunto(s)
Relojes Circadianos , Proteínas CLOCK , Diferenciación Celular , Ritmo Circadiano , HomeostasisRESUMEN
The planarian flatworm has become one of the leading animal model systems for studying stem cell behavior and tissue regeneration. Recent studies have shown that components of the circadian clockwork have important roles in tissue homeostasis and repair. However, it remains unknown whether planarians exhibit circadian or diurnal rhythms in physiology or behavior. Here, we developed a behavioral assay to evaluate diurnal activity in planarians based upon their well-established propensity to swim away from light (negative phototaxis). We show evidence that the planarian Schmidtea mediterranea has diurnal variability in negative phototaxis as a function of daily variation in motility. We also demonstrate that variation in planarian motility over 48 h occurs with 24-h periodicity. Our data suggest that S. mediterranea may be a useful model for studying the interplay between the circadian system and tissue regeneration.
Asunto(s)
Ritmo Circadiano , Luz , Actividad Motora/efectos de la radiación , Fototaxis/fisiología , Planarias/fisiología , Planarias/efectos de la radiación , Análisis de Varianza , Animales , Fotofobia , NataciónRESUMEN
Zebrafish heart regeneration occurs through the activation of cardiomyocyte proliferation in areas of trauma. Here, we show that within 3 hr of ventricular injury, the entire endocardium undergoes morphological changes and induces expression of the retinoic acid (RA)-synthesizing enzyme raldh2. By one day posttrauma, raldh2 expression becomes localized to endocardial cells at the injury site, an area that is supplemented with raldh2-expressing epicardial cells as cardiogenesis begins. Induced transgenic inhibition of RA receptors or expression of an RA-degrading enzyme blocked regenerative cardiomyocyte proliferation. Injured hearts of the ancient fish Polypterus senegalus also induced and maintained robust endocardial and epicardial raldh2 expression coincident with cardiomyocyte proliferation, whereas poorly regenerative infarcted murine hearts did not. Our findings reveal that the endocardium is a dynamic, injury-responsive source of RA in zebrafish, and indicate key roles for endocardial and epicardial cells in targeting RA synthesis to damaged heart tissue and promoting cardiomyocyte proliferation.
Asunto(s)
Endocardio/metabolismo , Corazón/fisiología , Pericardio/metabolismo , Regeneración/fisiología , Tretinoina/metabolismo , Pez Cebra/fisiología , Animales , Animales Modificados Genéticamente , Evolución Biológica , Proliferación Celular , Endocardio/citología , Endocardio/lesiones , Corazón/anatomía & histología , Ratones , Datos de Secuencia Molecular , Miocitos Cardíacos/citología , Miocitos Cardíacos/fisiología , Pericardio/citología , Pericardio/lesiones , Retinal-Deshidrogenasa/genética , Retinal-Deshidrogenasa/metabolismo , Transducción de Señal/fisiología , Pez Cebra/anatomía & histología , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
The heart maintains structural and functional integrity during years of continual contraction, but the extent to which new cell creation participates in cardiac homeostasis is unclear. Here, we assessed cellular and molecular mechanisms of cardiac homeostasis in zebrafish, which display indeterminate growth and possess an unusual capacity to regenerate after acute cardiac injury. Lowering fish density in the aquarium triggered rapid animal growth and robust cardiomyocyte proliferation throughout the adult ventricle, greater than that observed during slow animal growth or size maintenance. Rapid animal growth also induced strong expression of the embryonic epicardial markers raldh2 (aldh1a2) and tbx18 in adult epicardial tissue. Pulse-chase dye labeling experiments revealed that the epicardium recurrently contributes cells to the ventricular wall, indicating an active homeostatic process. Inhibition of signaling by Fibroblast growth factors (Fgfs) decreased this epicardial supplementation of the ventricular wall in growing zebrafish, and led to spontaneous ventricular scarring in animals maintaining cardiac size. Our results demonstrate that the adult zebrafish ventricle grows and is maintained by cardiomyocyte hyperplasia, and that epicardial cells are added to the ventricle in an Fgf-dependent fashion to support homeostasis.
Asunto(s)
Envejecimiento/fisiología , Células Epiteliales , Corazón/crecimiento & desarrollo , Homeostasis , Pez Cebra/crecimiento & desarrollo , Animales , Células Epiteliales/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Hiperplasia/patología , Miocardio/metabolismo , Transducción de Señal , Células Madre , Pez Cebra/metabolismoRESUMEN
Heart disease remains the leading cause of mortality throughout the world. Mammals have an extremely limited capacity to repair lost or damaged heart tissue, thus encouraging biologists to seek out models for heart regeneration. Zebrafish exhibit a robust regenerative capacity in a variety of tissues including the fin, spinal cord, retina, and heart, making it the sole regenerative vertebrate organism currently amenable to genetic manipulation. Future studies will utilize functional approaches to tease apart zebrafish heart regeneration in hopes of unlocking our own regenerative potential.
RESUMEN
As organisms develop, their tissues can become separated into distinct cell populations through the establishment of compartment boundaries. Compartment boundaries have been discovered in a wide variety of tissues, but in many cases the molecular mechanisms that separate cells remain poorly understood. In the Drosophila wing, a stripe of Notch activation maintains the dorsal-ventral compartment boundary, through a process that depends on the actin cytoskeleton. Here, we show that the dorsal-ventral boundary exhibits a distinct accumulation of Myosin II, and that this accumulation is regulated downstream of Notch signaling. Conversely, the dorsal-ventral boundary is depleted for the Par-3 homologue Bazooka. We further show that mutations in the Myosin heavy chain subunit encoded by zipper can impair dorsal-ventral compartmentalization without affecting anterior-posterior compartmentalization. These observations identify a distinct accumulation and requirement for Myosin activity in dorsal-ventral compartmentalization, and suggest a novel mechanism in which contractile tension along an F-actin cable at the compartment boundary contributes to compartmentalization.
Asunto(s)
Proteínas de Drosophila/genética , Drosophila/química , Proteínas de la Membrana/genética , Cadenas Pesadas de Miosina/genética , Miosina Tipo II/análisis , Receptores Notch/metabolismo , Alas de Animales/química , Animales , Drosophila/genética , Drosophila/crecimiento & desarrollo , Proteínas de Drosophila/análisis , Péptidos y Proteínas de Señalización Intracelular/análisis , Proteínas de la Membrana/análisis , Mutación , Cadenas Pesadas de Miosina/análisis , Miosina Tipo II/metabolismo , Alas de Animales/crecimiento & desarrolloRESUMEN
Compartment boundaries play key roles in tissue organization by separating cell populations. Activation of the Notch receptor is required for dorsoventral (DV) compartmentalization of the Drosophila wing, but the nature of its requirement has been controversial. Here, we provide additional evidence that a stripe of Notch activation is sufficient to establish a sharp separation between cell populations, irrespective of their dorsal or ventral identities. We further find that cells at the DV compartment boundary are characterized by a distinct shape, a smooth interface, and an accumulation of F-actin at the adherens junction. Genetic manipulation establishes that a stripe of Notch activation is both necessary and sufficient for this DV boundary cell phenotype, and supports the existence of a non-transcriptional branch of the Notch pathway that influences F-actin. Finally, we identify a distinct requirement for a regulator of actin polymerization, capulet, in DV compartmentalization. These observations imply that Notch effects compartmentalization through a novel mechanism, which we refer to as a fence, that does not depend on the establishment of compartment-specific cell affinities, but does depend on the organization of the actin cytoskeleton.