Genetic Analysis of Inner Ear Development in Xenopus tropicalis

University Of California Berkeley, Berkeley CA

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Abstract

DESCRIPTION (provided by applicant): Deficits in hearing or balance are common, and result from both developmental and environmental causes. In order to understand normal inner ear development, we will use the genetically tractable frog, Xenopus tropicalis, to investigate the genetic network underlying ear development. The structure and development of the inner ear shows conserved features among the vertebrates, and the development of the ear of the tetrapod is very similar to that of mammals. The relevant stages of ear development can be observed in the optically clear tadpole, making this animal ideal for genetic screens for ear mutants. Furthermore, defects in ear development lead to abnormal swimming behavior and loss of the righting response, so that defects that may not be anatomically obvious can also be scored. In response to PA-06-365, Cell Lineage and Developmental Studies in Hearing and Balance we have addressed the stated need for more comprehensive representation of model organisms systems to study ear development. We propose to advance our understanding of ear development by examining otic vesicle development in the tetrapod Xenopus tropicalis, an amphibian whose inner ear development is well-conserved with mammals. In a small-scale forward genetic screen using Xenopus tropicalis we have recovered mutants that disrupt ear morphology, otolith formation, and balancing/swimming behavior. We have isolated the affected gene in two of these that affect otoconial development and otocyst size. Thus we have shown that it is possible to screen for and recover mutants, analyze the phenotype, and map and clone the affected genes. The genome of X. tropicalis shows considerable structural similarity and synteny with mammalian genomes, with no sign of additional whole genome duplications, so we are confident that we can identify recessive mutants in a variety of genes which show conserved functions with the mammals. With recent improvements in the genome assembly and annotation, and technical advances in exon capture and high throughput sequence analysis, we are confident that other mutations can be rapidly mapped, and the affected genes isolated. In the next grant period, we propose to characterize additional mutant alleles by positional cloning, and link mutant phenotypes with the underlying molecular and cellular defects. We combine molecular approaches with classical embryological transplantations to understand the cel autonomy of mutants, and the signaling and responding tissues that interact to produce the functioning ear.