We still know very little about the mechanisms that regulate and synchronize morphogenetic events during later stages of vertebrate development. Nonetheless, understanding the factors controlling these later developmental periods is essential to understanding how adult traits form, and will lend insight into morphological defects and disorders that arise during human post-embryonic fetal and neonatal periods. This research utilizes the zebrafish, which undergoes extensive post-embryonic development involving modifications and maturation in many different organ systems;many of these changes are similar or identical to processes that occur following embryogenesis in humans. This proposal employs several strategies towards understanding the mechanisms underlying the zebrafish transformation from larva to juvenile.
The first aim adopts a targeted approach, testing the specific roles of thyroid hormone in post-embryonic developmental transitions. Multiple lines of evidence indicate that thyroid hormone is involved in several developmental processes in zebrafish, but the ability of this hormone to effect specific morphogenetic processes and cellular behaviors remains unclear.
This aim will test roles of thyroid hormone in promoting both global somatic developmental progression and the behaviors of a specific, well-characterized cell lineage that produces adult pigmentation during the larval-to-juvenile transition.
The second aim takes a forward genetic strategy to identify novel genes required for post-embryonic stage transitions. This approach has already identified two mutants that exhibit complete somatic arrest during larval development, ceasing ontogenetic progression at stages normally reached by 2- and 3-week old wild-type larvae. These phenotypes suggest an impairment of genes absolutely required for post-embryonic progression. Mapping and cloning the mutations and characterizing the pathways to which they belong will reveal mechanisms essential for post-embryonic developmental processes;continuation of this screen will identify further larval arrest phenotypes.
The final aim utilizes a species related to zebrafish that exhibits a natural failure t execute the terminal stages of somatic post-embryonic development. Focusing primarily on the structure and expression within the skin, changes in genetic and developmental architecture will be elucidated in this context of post-embryonic developmental truncation. These analyses will reveal the both extent of decoupling between traits and regulatory pathways, and whether dormant genetic pathways retain responsiveness to a key endocrine mediator of post-embryonic development. Overall, these efforts will characterize the morphogenetic roles of a known endocrine regulator, will identify novel factors that regulate normal post-embryonic progression, and will establish a novel model for dissecting the ways in which developmental genetic pathways and endocrine mechanisms can evolve. Moreover, this project will complete the developmental biology and genetics training of a scholar with a background in population ecology, and will establish the foundation for her independent research laboratory.

Public Health Relevance

The larval-to-adult transformation in zebrafish includes many processes similar or identical to those occurring in human embryonic, fetal and neonatal development;despite clear biomedical relevance, we know very little about the mechanisms controlling and synchronizing the processes that occur during these transitional periods. The proposed research will characterize the specific roles of thyroid hormone in post-embryonic developmental progression, will identify genes and pathways required for the development of adult characters, and will examine developmental and regulatory pathways in the context of natural developmental truncation.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Career Transition Award (K99)
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Special Emphasis Panel (ZGM1-TRN-X (KR))
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Hamlet, Michelle R
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University of Washington
Schools of Arts and Sciences
United States
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Hur, Matthew; Gistelinck, Charlotte A; Huber, Philippe et al. (2017) MicroCT-based phenomics in the zebrafish skeleton reveals virtues of deep phenotyping in a distributed organ system. Elife 6:
McMenamin, S K; Chandless, M N; Parichy, D M (2016) Working with zebrafish at postembryonic stages. Methods Cell Biol 134:587-607
McMenamin, Sarah K; Bain, Emily J; McCann, Anna E et al. (2014) Thyroid hormone-dependent adult pigment cell lineage and pattern in zebrafish. Science 345:1358-61