RESUMEN
The vertebrate hindbrain develops from a series of segments (rhombomeres) distributed along the anteroposterior axis. We are studying the roles of Wnt and Delta-Notch signaling in maintaining rhombomere boundaries as organizing centers in the zebrafish hindbrain. Several wnt genes (wnt1, wnt3a, wnt8b, and wnt10b) show elevated expression at rhombomere boundaries, whereas several delta genes (dlA, dlB, and dlD) are expressed in transverse stripes flanking rhombomere boundaries. Partial disruption of Wnt signaling by knockdown of multiple wnt genes, or the Wnt mediator tcf3b, ablates boundaries and associated cell types. Expression of dlA is chaotic, and cell types associated with rhombomere centers are disorganized. Similar patterning defects are observed in segmentation mutants spiel-ohne-grenzen (spg) and valentino (val), which fail to form rhombomere boundaries due to faulty interactions between adjacent rhombomeres. Stripes of wnt expression are variably disrupted, with corresponding disturbances in metameric patterning. Mutations in dlA or mind bomb (mib) disrupt Delta-Notch signaling and cause a wide range of patterning defects in the hindbrain. Stripes of wnt1 are initially normal but subsequently dissipate, and metameric patterning becomes increasingly disorganized. Driving wnt1 expression using a heat-shock construct partially rescues metameric patterning in mib mutants. Thus, rhombomere boundaries act as Wnt signaling centers required for precise metameric patterning, and Delta signals from flanking cells provide feedback to maintain wnt expression at boundaries. Similar feedback mechanisms operate in the Drosophila wing disc and vertebrate limb bud, suggesting coaptation of a conserved signaling module that spatially organizes cells in complex organ systems.
Asunto(s)
Tipificación del Cuerpo , Estructuras Embrionarias/fisiología , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Morfogénesis , Rombencéfalo/embriología , Transducción de Señal/fisiología , Animales , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Estructuras Embrionarias/anatomía & histología , Factor Nuclear 3-beta del Hepatocito , Hibridación in Situ , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intracelular , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Mutación , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Receptores Notch , Rombencéfalo/anatomía & histología , Rombencéfalo/fisiología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas Wnt , Proteína Wnt1 , Pez Cebra , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
Abstract Recent years have seen a renaissance of investigation into the mechanisms of inner ear development. Genetic analysis of zebrafish has contributed significantly to this endeavour, with several dramatic advances reported over the past year or two. Here, we review the major findings from recent work in zebrafish. Several cellular and molecular mechanisms have been elucidated, including the signaling pathways controlling induction of the otic placode, morphogenesis and patterning of the otic vesicle, and elaboration of functional attributes of inner ear.