Date of Award

Summer 8-18-2023

Level of Access Assigned by Author

Open-Access Thesis

Degree Name

Master of Science (MS)

Department

Biochemistry

Advisor

Jared Talbot

Second Committee Member

Clarissa Henry

Third Committee Member

Julie Gosse

Abstract

Hypaxial muscles form through long-range migration of muscle precursor cells (MMPs) from the somites. In zebrafish, the MMPs migrate in three compact streams to generate four muscles - the sternohyoideus muscle, homologous to mammalian neck and tongue; the posterior hypaxial muscle; and the two pectoral fin muscles, homologous to mammalian limbs. Several factors, such as Six1/4, are known to promote this migration; however, many aspects of guidance, pathing, and modulation of these streams are still unknown. To fill this gap, we conducted a small-molecule screen. This pharmacological approach allows us to identify molecules that cause pronounced changes in the normal pattern of MMP migration. Using a transgenic zebrafish line, six1b:lyn-GFP, we are able to visualize MMPs during development under treatment with pools of bioactive molecules and observe their effects. Fish are treated from 24 hours post fertilization (hpf), prior to migration, through 48 hpf, when the migrating cells begin to specify and generate muscle fibers. So far, we have tested over 800 small molecules and identified a dozen that cause promising effects. The screen has successfully generated new hypotheses concerning new cues - estrogen signaling, cholesterol synthesis - and new roles for known factors in development of these muscles - retinoic acid. In this thesis, I report the overall results of the small molecule screen and the new models developed using our findings.

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