RESUMEN
Cilia are organelles specialized in movement and signal transduction. The ciliary transient receptor potential ion channel polycystin-2 (TRPP2) controls elementary cilia-mediated physiological functions ranging from male fertility and kidney development to left-right patterning. However, the molecular components translating TRPP2 channel-mediated Ca2+ signals into respective physiological functions are unknown. Here, we show that the Ca2+-regulated mitochondrial ATP-Mg/Pi solute carrier 25 A 25 (SLC25A25) acts downstream of TRPP2 in an evolutionarily conserved metabolic signaling pathway. We identify SLC25A25 as an essential component in this cilia-dependent pathway using a genome-wide forward genetic screen in Drosophila melanogaster, followed by a targeted analysis of SLC25A25 function in zebrafish left-right patterning. Our data suggest that TRPP2 ion channels regulate mitochondrial SLC25A25 transporters via Ca2+ establishing an evolutionarily conserved molecular link between ciliary signaling and mitochondrial metabolism.
Asunto(s)
Sistemas de Transporte de Aminoácidos Acídicos/metabolismo , Proteínas de Unión al Calcio/metabolismo , Cilios/metabolismo , Canales Catiónicos TRPP/metabolismo , Animales , Antiportadores/metabolismo , Calcio/metabolismo , Canales de Calcio/metabolismo , Drosophila melanogaster/metabolismo , Heterocigoto , Humanos , Canales Iónicos/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Proteínas Mitocondriales/metabolismo , Transducción de Señal , Pez CebraRESUMEN
Hedgehog proteins constitute one of a small number of families of secreted signals that have a central role in the development of metazoans. Genetic analyses in flies, fish and mice have uncovered the major components of the pathway that transduces Hedgehog signals, and recent genome sequence projects have provided clues about its evolutionary origins. In this Review we provide an updated overview of the mechanisms and functions of this signalling pathway, highlighting the conserved and divergent features of the pathway, as well as some of the common themes in its deployment that have emerged from recent studies.
Asunto(s)
Regulación de la Expresión Génica , Proteínas Hedgehog/metabolismo , Animales , Cilios/metabolismo , Drosophila melanogaster , Genoma , Proteínas Hedgehog/genética , Humanos , Ligandos , Lípidos/química , Ratones , Modelos Genéticos , Filogenia , Estructura Terciaria de Proteína , Transducción de Señal , Factores de Transcripción/metabolismoRESUMEN
The transcription factor Pax7 is a marker and regulator of muscle progenitors and satellite cells that contribute to the embryonic development and postembryonic growth of skeletal muscle in vertebrates, as well as to its repair and regeneration. Here, we identify Pax7(+ve) myogenic cells in the zebrafish and characterize their behavior in postembryonic stages. Mononucleate Pax7(+ve) cells can first be found associated with myofibers at 72 hours post fertilization (hpf). To follow the behavior of muscle progenitor cells in vivo, we generated transgenic lines expressing fluorescent proteins under the control of the pax7a or pax3a promoters. We established an injury model using cardiotoxin injection and monitored cell proliferation and myogenic regulatory factor expression in myogenic precursors cells and muscle fibers after injury using proliferation markers and the transgenic lines. We also analyzed Pax7(+ve) cells in animals with dystrophic phenotypes and found an increased number compared with wild-type.