RESUMEN
Ventricular and atrial cardiac chambers have unique structural and contractile characteristics that underlie their distinct functions. The maintenance of chamber-specific features requires active reinforcement, even in differentiated cardiomyocytes. Previous studies in zebrafish have shown that sustained FGF signaling acts upstream of Nkx factors to maintain ventricular identity, but the rest of this maintenance pathway remains unclear. Here, we show that MEK1/2-ERK1/2 signaling acts downstream of FGF and upstream of Nkx factors to promote ventricular maintenance. Inhibition of MEK signaling, like inhibition of FGF signaling, results in ectopic atrial gene expression and reduced ventricular gene expression in ventricular cardiomyocytes. FGF and MEK signaling both influence ventricular maintenance over a similar timeframe, when phosphorylated ERK (pERK) is present in the myocardium. However, the role of FGF-MEK activity appears to be context-dependent: some ventricular regions are more sensitive than others to inhibition of FGF-MEK signaling. Additionally, in the atrium, although endogenous pERK does not induce ventricular traits, heightened MEK signaling can provoke ectopic ventricular gene expression. Together, our data reveal chamber-specific roles of MEK-ERK signaling in the maintenance of ventricular and atrial identities.
Asunto(s)
Sistema de Señalización de MAP Quinasas , Pez Cebra , Animales , Pez Cebra/genética , Pez Cebra/metabolismo , Transducción de Señal/genética , Miocitos Cardíacos/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismoRESUMEN
BACKGROUND: Essential patterning processes transform the heart tube into a compartmentalized organ with distinct chambers separated by an atrioventricular canal (AVC). This transition involves the refinement of expression of genes that are first found broadly throughout the heart tube and then become restricted to the AVC. Despite the importance of cardiac patterning, we do not fully understand the mechanisms that limit gene expression to the AVC. RESULTS: We show that the zebrafish gene smarcc1a, encoding a BAF chromatin remodeling complex subunit homologous to mammalian BAF155, is critical for cardiac patterning. In smarcc1a mutants, myocardial differentiation and heart tube assembly appear to proceed normally. Subsequently, the smarcc1a mutant heart fails to exhibit refinement of gene expression patterns to the AVC, and the persistence of broad gene expression is accompanied by failure of chamber expansion. In addition to their cardiac defects, smarcc1a mutants lack pectoral fins, indicating similarity to tbx5a mutants. However, comparison of smarcc1a and tbx5a mutants suggests that perturbation of tbx5a function is not sufficient to cause the smarcc1a mutant phenotype. CONCLUSIONS: Our data indicate an important role for Smarcc1a-containing chromatin remodeling complexes in regulating the changes in gene expression and morphology that distinguish the AVC from the cardiac chambers.
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Cojinetes Endocárdicos , Pez Cebra , Animales , Pez Cebra/genética , Pez Cebra/metabolismo , Ensamble y Desensamble de Cromatina , Proteínas de Pez Cebra/metabolismo , Corazón , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Regulación del Desarrollo de la Expresión Génica , Mamíferos/metabolismoRESUMEN
Support for basic science has been eclipsed by initiatives aimed at specific medical problems. The latest example is the dismantling of the Skirball Institute at NYU School of Medicine. Here, we reflect on the achievements and mission underlying the Skirball to gain insight into the dividends of maintaining a basic science vision within the academic enterprises.
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Academias e Institutos , Investigación Biomédica , Facultades de MedicinaRESUMEN
Transcriptional regulatory networks refine gene expression boundaries to define the dimensions of organ progenitor territories. Kidney progenitors originate within the intermediate mesoderm (IM), but the pathways that establish the boundary between the IM and neighboring vessel progenitors are poorly understood. Here, we delineate roles for the zinc-finger transcription factor Osr1 in kidney and vessel progenitor development. Zebrafish osr1 mutants display decreased IM formation and premature emergence of lateral vessel progenitors (LVPs). These phenotypes contrast with the increased IM and absent LVPs observed with loss of the bHLH transcription factor Hand2, and loss of hand2 partially suppresses osr1 mutant phenotypes. hand2 and osr1 are expressed together in the posterior mesoderm, but osr1 expression decreases dramatically prior to LVP emergence. Overexpressing osr1 during this timeframe inhibits LVP development while enhancing IM formation, and can rescue the osr1 mutant phenotype. Together, our data demonstrate that osr1 modulates the extent of IM formation and the temporal dynamics of LVP development, suggesting that a balance between levels of osr1 and hand2 expression is essential to demarcate the kidney and vessel progenitor territories.
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Diferenciación Celular/fisiología , Mesodermo/metabolismo , Mesodermo/fisiología , Proteínas de Pez Cebra/metabolismo , Pez Cebra/metabolismo , Pez Cebra/fisiología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Regulación del Desarrollo de la Expresión Génica/fisiología , Riñón/metabolismo , Riñón/fisiología , Organogénesis/fisiología , Factores de Transcripción/metabolismoRESUMEN
The vertebrate heart is comprised of two types of chambers-ventricles and atria-that have unique morphological and physiological properties. Effective cardiac function depends upon the distinct characteristics of ventricular and atrial cardiomyocytes, raising interest in the genetic pathways that regulate chamber-specific traits. Chamber identity seems to be specified in the early embryo by signals that establish ventricular and atrial progenitor populations and trigger distinct differentiation pathways. Intriguingly, chamber-specific features appear to require active reinforcement, even after myocardial differentiation is underway, suggesting plasticity of chamber identity within the developing heart. Here, we review the utility of the zebrafish as a model organism for studying the mechanisms that establish and maintain cardiac chamber identity. By combining genetic and embryological approaches, work in zebrafish has revealed multiple players with potent influences on chamber fate specification and commitment. Going forward, analysis of cardiomyocyte identity at the single-cell level is likely to yield a high-resolution understanding of the pathways that link the relevant players together, and these insights will have the potential to inform future strategies in cardiac tissue engineering.
RESUMEN
Organ maturation entails the reshaping of simple tissues into more complex structures critical for function. In a recent issue of Nature, Priya et al. show how tension heterogeneity between developing cardiomyocytes can coordinate the cell behaviors that remodel the architecture of the cardiac chamber wall.
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Miocardio , Distanciamiento Físico , Morfogénesis , Miocitos Cardíacos , OrganogénesisRESUMEN
Haematopoietic stem and progenitor cells (HSPCs) have been the focus of developmental and regenerative studies, yet our understanding of the signalling events regulating their specification remains incomplete. We demonstrate that supt16h, a component of the Facilitates chromatin transcription (FACT) complex, is required for HSPC formation. Zebrafish supt16h mutants express reduced levels of Notch-signalling components, genes essential for HSPC development, due to abrogated transcription. Whereas global chromatin accessibility in supt16h mutants is not substantially altered, we observe a specific increase in p53 accessibility, causing an accumulation of p53. We further demonstrate that p53 influences expression of the Polycomb-group protein PHC1, which functions as a transcriptional repressor of Notch genes. Suppression of phc1 or its upstream regulator, p53, rescues the loss of both Notch and HSPC phenotypes in supt16h mutants. Our results highlight a relationship between supt16h, p53 and phc1 to specify HSPCs via modulation of Notch signalling.
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Proteínas de Ciclo Celular/genética , Células Madre Hematopoyéticas/metabolismo , Receptores Notch/genética , Factores de Transcripción/genética , Proteína p53 Supresora de Tumor/genética , Proteínas de Pez Cebra/genética , Pez Cebra/genética , Animales , Animales Modificados Genéticamente , Proteínas de Ciclo Celular/metabolismo , Perfilación de la Expresión Génica/métodos , Regulación del Desarrollo de la Expresión Génica , Ontología de Genes , Células Madre Hematopoyéticas/citología , Mutación , Complejo Represivo Polycomb 1/genética , Complejo Represivo Polycomb 1/metabolismo , Receptores Notch/metabolismo , Factores de Transcripción/metabolismo , Transcripción Genética , Proteína p53 Supresora de Tumor/metabolismo , Pez Cebra/embriología , Pez Cebra/crecimiento & desarrollo , Proteínas de Pez Cebra/metabolismoRESUMEN
Physical forces are important participants in the cellular dynamics that shape developing organs. During heart formation, for example, contractility and blood flow generate biomechanical cues that influence patterns of cell behavior. Here, we address the interplay between function and form during the assembly of the cardiac outflow tract (OFT), a crucial connection between the heart and vasculature that develops while circulation is under way. In zebrafish, we find that the OFT expands via accrual of both endocardial and myocardial cells. However, when cardiac function is disrupted, OFT endocardial growth ceases, accompanied by reduced proliferation and reduced addition of cells from adjacent vessels. The flow-responsive TGFß receptor Acvrl1 is required for addition of endocardial cells, but not for their proliferation, indicating distinct modes of function-dependent regulation for each of these essential cell behaviors. Together, our results indicate that cardiac function modulates OFT morphogenesis by triggering endocardial cell accumulation that induces OFT lumen expansion and shapes OFT dimensions. Moreover, these morphogenetic mechanisms provide new perspectives regarding the potential causes of cardiac birth defects.
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Endocardio/metabolismo , Corazón/fisiología , Pez Cebra/metabolismo , Receptores de Activinas/antagonistas & inhibidores , Receptores de Activinas/genética , Receptores de Activinas/metabolismo , Animales , Animales Modificados Genéticamente/crecimiento & desarrollo , Animales Modificados Genéticamente/metabolismo , Proliferación Celular , Embrión no Mamífero/citología , Embrión no Mamífero/metabolismo , Endocardio/citología , Corazón/anatomía & histología , Corazón/crecimiento & desarrollo , Morfolinos/metabolismo , Troponina T/antagonistas & inhibidores , Troponina T/genética , Troponina T/metabolismo , Pez Cebra/crecimiento & desarrollo , Proteínas de Pez Cebra/antagonistas & inhibidores , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
BACKGROUND: The self-assembly of metabolic enzymes into filaments or foci highlights an intriguing mechanism for the regulation of metabolic activity. Recently, we identified the conserved polymerization of phosphoribosyl pyrophosphate synthetase (PRPS), which catalyzes the first step in purine nucleotide synthesis, in yeast and cultured mammalian cells. While previous work has revealed that loss of PRPS activity regulates retinal development in zebrafish, the extent to which PRPS filament formation affects tissue development remains unknown. RESULTS: By generating novel alleles in the zebrafish PRPS paralogs, prps1a and prps1b, we gained new insight into the role of PRPS filaments during eye development. We found that mutations in prps1a alone are sufficient to generate abnormally small eyes along with defects in head size, pigmentation, and swim bladder inflation. Furthermore, a loss-of-function mutation that truncates the Prps1a protein resulted in the failure of PRPS filament assembly. Lastly, in mutants that fail to assemble PRPS filaments, we observed disorganization of the actin network in the lens fibers. CONCLUSIONS: The truncation of Prps1a blocked PRPS filament formation and resulted in a disorganized lens fiber actin network. Altogether, these findings highlight a potential role for PRPS filaments during lens fiber organization in zebrafish.
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Cristalino/embriología , Cristalino/crecimiento & desarrollo , Ribosa-Fosfato Pirofosfoquinasa/genética , Ribosa-Fosfato Pirofosfoquinasa/metabolismo , Proteínas de Pez Cebra/metabolismo , Pez Cebra/embriología , Actinas/metabolismo , Sacos Aéreos/embriología , Alelos , Animales , Ojo/embriología , Ojo/crecimiento & desarrollo , Regulación del Desarrollo de la Expresión Génica , Genotipo , Microscopía Fluorescente , Mutación , Pigmentación , Polimerizacion , Retina/embriología , Epitelio Pigmentado de la Retina/embriología , Pez Cebra/genética , Proteínas de Pez Cebra/genéticaAsunto(s)
Corazón/embriología , Miocardio/metabolismo , Animales , Embrión de Pollo , Biología Evolutiva/métodos , HumanosRESUMEN
Intra-organ communication guides morphogenetic processes that are essential for an organ to carry out complex physiological functions. In the heart, the growth of the myocardium is tightly coupled to that of the endocardium, a specialized endothelial tissue that lines its interior. Several molecular pathways have been implicated in the communication between these tissues including secreted factors, components of the extracellular matrix, or proteins involved in cell-cell communication. Yet, it is unknown how the growth of the endocardium is coordinated with that of the myocardium. Here, we show that an increased expansion of the myocardial atrial chamber volume generates higher junctional forces within endocardial cells. This leads to biomechanical signaling involving VE-cadherin, triggering nuclear localization of the Hippo pathway transcriptional regulator Yap1 and endocardial proliferation. Our work suggests that the growth of the endocardium results from myocardial chamber volume expansion and ends when the tension on the tissue is relaxed.
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Endocardio/crecimiento & desarrollo , Miocardio/metabolismo , Transducción de Señal , Pez Cebra/embriología , Animales , Antígenos CD/metabolismo , Fenómenos Biomecánicos , Cadherinas/metabolismo , Núcleo Celular/metabolismo , Proliferación Celular , Tamaño de la Célula , Proteínas del Citoesqueleto/metabolismo , Endocardio/citología , Atrios Cardíacos/citología , Atrios Cardíacos/metabolismo , Proteína Homeótica Nkx-2.5/metabolismo , Uniones Intercelulares/metabolismo , Modelos Biológicos , Mutación/genética , Transactivadores/metabolismo , Proteínas Wnt/metabolismo , Proteínas Señalizadoras YAP , Proteínas de Pez Cebra/metabolismoRESUMEN
Pacemaker cardiomyocytes that create the sinoatrial node are essential for the initiation and maintenance of proper heart rhythm. However, illuminating developmental cues that direct their differentiation has remained particularly challenging due to the unclear cellular origins of these specialized cardiomyocytes. By discovering the origins of pacemaker cardiomyocytes, we reveal an evolutionarily conserved Wnt signaling mechanism that coordinates gene regulatory changes directing mesoderm cell fate decisions, which lead to the differentiation of pacemaker cardiomyocytes. We show that in zebrafish, pacemaker cardiomyocytes derive from a subset of Nkx2.5+ mesoderm that responds to canonical Wnt5b signaling to initiate the cardiac pacemaker program, including activation of pacemaker cell differentiation transcription factors Isl1 and Tbx18 and silencing of Nkx2.5. Moreover, applying these developmental findings to human pluripotent stem cells (hPSCs) notably results in the creation of hPSC-pacemaker cardiomyocytes, which successfully pace three-dimensional bioprinted hPSC-cardiomyocytes, thus providing potential strategies for biological cardiac pacemaker therapy.
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Proteína Homeótica Nkx-2.5/metabolismo , Mesodermo/metabolismo , Miocitos Cardíacos/metabolismo , Transducción de Señal , Proteínas Wnt/metabolismo , Animales , Secuencia de Bases , Bioimpresión , Diferenciación Celular , Regulación del Desarrollo de la Expresión Génica , Humanos , Mutación con Pérdida de Función/genética , Modelos Cardiovasculares , Miocitos Cardíacos/citología , Células Madre Pluripotentes/citología , Células Madre Pluripotentes/metabolismo , Células Madre/metabolismo , Pez CebraRESUMEN
BACKGROUND: Atrioventricular valve development relies upon the precisely defined dimensions of the atrioventricular canal (AVC). Current models suggest that Wnt signaling plays an important role atop a pathway that promotes AVC development. The factors that confine AVC differentiation to the appropriate location, however, are less well understood. RESULTS: Transmembrane protein 2 (Tmem2) is a key player in restricting AVC differentiation: in zebrafish, tmem2 mutants display an expansion of AVC characteristics, but the molecular mechanism of Tmem2 function in this context remains unclear. Through structure-function analysis, we demonstrate that the extracellular portion of Tmem2 is crucial for its role in restricting AVC boundaries. Importantly, the Tmem2 ectodomain contains regions implicated in the depolymerization of hyaluronic acid (HA). We find that tmem2 mutant hearts exhibit excess HA deposition alongside broadened distribution of Wnt signaling. Moreover, addition of ectopic hyaluronidase can restore the restriction of AVC differentiation in tmem2 mutants. Finally, we show that alteration of a residue important for HA depolymerization impairs the efficacy of Tmem2 function during AVC development. CONCLUSIONS: Taken together, our data support a model in which HA degradation, regulated by Tmem2, limits the distribution of Wnt signaling and thereby confines the differentiation of the AVC.
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Defectos de los Tabiques Cardíacos/genética , Tabiques Cardíacos/embriología , Ventrículos Cardíacos/embriología , Ácido Hialurónico/metabolismo , Proteínas de la Membrana/fisiología , Proteínas de Pez Cebra/fisiología , Animales , Animales Modificados Genéticamente , Metabolismo de los Hidratos de Carbono/genética , Embrión no Mamífero , Corazón/embriología , Defectos de los Tabiques Cardíacos/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Organogénesis/genética , Transducción de Señal/genética , Vía de Señalización Wnt/genética , Pez Cebra/embriología , Pez Cebra/genética , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
Ionocytes are specialized cells in the epidermis of embryonic zebrafish (Danio rerio) that play important roles in ion homeostasis and have functional similarities to mammalian renal cells. Here, we examined whether these cells might also share another functional similarity with renal cells, which is the presence of efflux transporter activities useful for elimination of toxic small molecules. Xenobiotic transporters (XTs), including the ATP-Binding Cassette (ABC) family, are a major defense mechanism against diffusible toxic molecules in aquatic embryos, including zebrafish, but their activity in the ionocytes has not previously been studied. Using fluorescent small molecule substrates of XT, we observed that specific populations of ionocytes uptake and efflux fluorescent small molecules in a manner consistent with active transport. We specifically identified a P-gp/ABCB1 inhibitor-sensitive efflux activity in the H+-ATPase-rich (HR) ionocytes, and show that these cells exhibit enriched expression of the ABCB gene, abcb5. The results extend our understanding of the functional significance of zebrafish ionocytes and indicate that these cells could play an important role in protection of the fish embryo from harmful small molecules.
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Embrión no Mamífero/citología , Embrión no Mamífero/metabolismo , Xenobióticos/metabolismo , Proteínas de Pez Cebra/metabolismo , Pez Cebra/embriología , Pez Cebra/metabolismo , Animales , Aniones , Transporte Biológico , Epidermis/efectos de los fármacos , Colorantes Fluorescentes/metabolismo , Mitocondrias/metabolismo , ATPasas de Translocación de Protón/metabolismo , Proteínas de Pez Cebra/genéticaRESUMEN
Heart formation involves a complex series of tissue rearrangements, during which regions of the developing organ expand, bend, converge, and protrude in order to create the specific shapes of important cardiac components. Much of this morphogenesis takes place while cardiac function is underway, with blood flowing through the rapidly contracting chambers. Fluid forces are therefore likely to influence the regulation of cardiac morphogenesis, but it is not yet clear how these biomechanical cues direct specific cellular behaviors. In recent years, the optical accessibility and genetic amenability of zebrafish embryos have facilitated unique opportunities to integrate the analysis of flow parameters with the molecular and cellular dynamics underlying cardiogenesis. Consequently, we are making progress toward a comprehensive view of the biomechanical regulation of cardiac chamber emergence, atrioventricular canal differentiation, and ventricular trabeculation. In this review, we highlight a series of studies in zebrafish that have provided new insight into how cardiac function can shape cardiac morphology, with a particular focus on how hemodynamics can impact cardiac cell behavior. Over the long-term, this knowledge will undoubtedly guide our consideration of the potential causes of congenital heart disease.
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Líquidos Corporales/fisiología , Corazón/embriología , Corazón/fisiología , Morfogénesis , Pez Cebra/embriología , Animales , Fenómenos Biomecánicos , Diferenciación Celular/genética , Cojinetes Endocárdicos/citología , Cojinetes Endocárdicos/embriología , Cojinetes Endocárdicos/metabolismo , Endocardio/citología , Endocardio/embriología , Endocardio/metabolismo , Regulación del Desarrollo de la Expresión Génica , Corazón/anatomía & histología , Pez Cebra/genéticaRESUMEN
Atrial and ventricular cardiac chambers behave as distinct subunits with unique morphological, electrophysiological and contractile properties. Despite the importance of chamber-specific features, chamber fate assignments remain relatively plastic, even after differentiation is underway. In zebrafish, Nkx transcription factors are essential for the maintenance of ventricular characteristics, but the signaling pathways that operate upstream of Nkx factors in this context are not well understood. Here, we show that FGF signaling plays an essential part in enforcing ventricular identity. Loss of FGF signaling results in a gradual accumulation of atrial cells, a corresponding loss of ventricular cells, and the appearance of ectopic atrial gene expression within the ventricle. These phenotypes reflect important roles for FGF signaling in promoting ventricular traits, both in early-differentiating cells that form the initial ventricle and in late-differentiating cells that append to its arterial pole. Moreover, we find that FGF signaling functions upstream of Nkx genes to inhibit ectopic atrial gene expression. Together, our data suggest a model in which sustained FGF signaling acts to suppress cardiomyocyte plasticity and to preserve the integrity of the ventricular chamber.
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Factores de Crecimiento de Fibroblastos/metabolismo , Ventrículos Cardíacos/embriología , Ventrículos Cardíacos/metabolismo , Organogénesis , Transducción de Señal , Pez Cebra/embriología , Pez Cebra/metabolismo , Animales , Diferenciación Celular , Embrión no Mamífero/citología , Embrión no Mamífero/metabolismo , Regulación del Desarrollo de la Expresión Génica , Atrios Cardíacos/citología , Ventrículos Cardíacos/citología , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Organogénesis/genética , Transducción de Señal/genética , Factores de Tiempo , Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
Communication between neighboring tissues plays a central role in guiding organ morphogenesis. During heart tube assembly, interactions with the adjacent endoderm control the medial movement of cardiomyocytes, a process referred to as cardiac fusion. However, the molecular underpinnings of this endodermal-myocardial relationship remain unclear. Here, we show an essential role for platelet-derived growth factor receptor alpha (Pdgfra) in directing cardiac fusion. Mutation of pdgfra disrupts heart tube assembly in both zebrafish and mouse. Timelapse analysis of individual cardiomyocyte trajectories reveals misdirected cells in zebrafish pdgfra mutants, suggesting that PDGF signaling steers cardiomyocytes toward the midline during cardiac fusion. Intriguingly, the ligand pdgfaa is expressed in the endoderm medial to the pdgfra-expressing myocardial precursors. Ectopic expression of pdgfaa interferes with cardiac fusion, consistent with an instructive role for PDGF signaling. Together, these data uncover a novel mechanism through which endodermal-myocardial communication can guide the cell movements that initiate cardiac morphogenesis.
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Movimiento Celular , Corazón/embriología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/fisiología , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Transducción de Señal , Animales , Técnicas de Inactivación de Genes , Ratones , Morfogénesis , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Imagen de Lapso de Tiempo , Pez CebraRESUMEN
In gnathostomes, dorsoventral (D-V) patterning of neural crest cells (NCC) within the pharyngeal arches is crucial for the development of hinged jaws. One of the key signals that mediate this process is Endothelin-1 (EDN1). Loss of EDN1 binding to the Endothelin-A receptor (EDNRA) results in loss of EDNRA signaling and subsequent facial birth defects in humans, mice and zebrafish. A rate-limiting step in this crucial signaling pathway is the conversion of immature EDN1 into a mature active form by Endothelin converting enzyme-1 (ECE1). However, surprisingly little is known about how Ece1 transcription is induced or regulated. We show here that Nkx2.5 is required for proper craniofacial development in zebrafish and acts in part by upregulating ece1 expression. Disruption of nkx2.5 in zebrafish embryos results in defects in both ventral and dorsal pharyngeal arch-derived elements, with changes in ventral arch gene expression consistent with a disruption in Ednra signaling. ece1 mRNA rescues the nkx2.5 morphant phenotype, indicating that Nkx2.5 functions through modulating Ece1 expression or function. These studies illustrate a new function for Nkx2.5 in embryonic development and provide new avenues with which to pursue potential mechanisms underlying human facial disorders.
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Enzimas Convertidoras de Endotelina/genética , Regulación del Desarrollo de la Expresión Génica , Proteína Homeótica Nkx-2.5/genética , Cresta Neural/metabolismo , Proteínas de Pez Cebra/genética , Animales , Enzimas Convertidoras de Endotelina/metabolismo , Proteína Homeótica Nkx-2.5/metabolismo , Ratones , Cresta Neural/embriología , Faringe/embriología , Faringe/metabolismo , Regulación hacia Arriba , Pez Cebra , Proteínas de Pez Cebra/metabolismoRESUMEN
Proper organogenesis depends upon defining the precise dimensions of organ progenitor territories. Kidney progenitors originate within the intermediate mesoderm (IM), but the pathways that set the boundaries of the IM are poorly understood. Here, we show that the bHLH transcription factor Hand2 limits the size of the embryonic kidney by restricting IM dimensions. The IM is expanded in zebrafish hand2 mutants and is diminished when hand2 is overexpressed. Within the posterior mesoderm, hand2 is expressed laterally adjacent to the IM. Venous progenitors arise between these two territories, and hand2 promotes venous development while inhibiting IM formation at this interface. Furthermore, hand2 and the co-expressed zinc-finger transcription factor osr1 have functionally antagonistic influences on kidney development. Together, our data suggest that hand2 functions in opposition to osr1 to balance the formation of kidney and vein progenitors by regulating cell fate decisions at the lateral boundary of the IM.