The goal of this project is to determine the role that muscle-specific microRNAs (miRNA) play in vivo to regulate somite and muscle morphogenesis in the frog, Xenopus laevis. miRNAs are small, non-coding sequences of RNA that regulate genes post-transcriptionally by binding specific messenger RNA and blocking its translation. They have been shown to play a major role in embryogenesis and diseases. Of particular interest are three muscle-specific RNAs, miR-1, miR-206 and miR-133, which play an important role in the formation and maintenance of cardiac and skeletal muscle tissue. These miRNAs have been linked to several different muscle-related diseases. Although there is growing interest in the role of these miRNAs in development and disease, very few in-vivo studies have been conducted to date. Thus, our lab has begun to examine the role of miR-206 using Xenopus laevis as our model system. Our preliminary studies indicate that miR-206 is expressed in the paraxial mesoderm at the right time and place to mediate muscle development. Further, knockdown of miR-206 expression leads to significant defects in segmentation, somite formation and muscle cell elongation and alignment. Given that each miRNA is predicted to regulate different targets, we hypothesize that these three miRNAs have both unique and complementary roles in regulating the cell behaviors that underlie embryonic somite and muscle morphogenesis. We will test this hypothesis using a combination of cell and molecular approaches to examine: the impact of knocking down each miRNA on somite and muscle morphogenesis (Aim 1);the impact of overexpressing each miRNA on the morphogenetic movements underlying somite and muscle formation (Aim 2);and the combinatorial roles of miR-1, miR-206 and miR-133 on morphogenesis (Aim 3). Collectively, this work will provide a comprehensive in vivo examination of the role of these three miRNAs on somite and muscle formation during embryogenesis and will also identify cellular mechanisms that are important in this morphological process that are regulated by these miRNAs. This SC-3 project will further the PI's development through ongoing collaboration with the Harland laboratory at UC Berkeley, a premier Xenopus lab that has developed many cutting edge tools for investigating gene regulation during Xenopus embryonic development. With the help of this collaborative effort and the requested funding, the PI will increase her research productivity in order to transition to mainstream funding. The project will also provide research training opportunities in an important field of study for large numbers of undergraduate and master's students, primarily underrepresented minorities, at one of the nation's most culturally diverse comprehensive public universities.

Public Health Relevance

We propose studying the role of three muscle-specific microRNA, miR-1, miR-206, and miR-133 during somite and muscle formation in the frog, X. laevis. These microRNAs have been shown to play a role in several diseases such as muscular dystrophy, amyotrophic lateral sclerosis, rhabdomyosarcoma and several types of cancer. Our findings will advance the understanding of cellular processes regulated by these microRNAs during vertebrate embryogenesis as well as contribute to our understanding of the role of these microRNAs in specific muscle-related diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Continuance Award (SC3)
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Special Emphasis Panel (ZGM1)
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Zlotnik, Hinda
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San Francisco State University
Schools of Arts and Sciences
San Francisco
United States
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Vergara, Hernando Martínez; Ramirez, Julio; Rosing, Trista et al. (2018) miR-206 is required for changes in cell adhesion that drive muscle cell morphogenesis in Xenopus laevis. Dev Biol 438:94-110
Sabillo, Armbien; Ramirez, Julio; Domingo, Carmen R (2016) Making muscle: Morphogenetic movements and molecular mechanisms of myogenesis in Xenopus laevis. Semin Cell Dev Biol 51:80-91