The vertebrate segmentation clock is a model biological oscillator that generates periodic pattern in developing embryos. The segmentation clock controls somitogenesis, the process by which the mesoderm of the vertebrate animal is sequentially divided into segmental units called somites. At the core of the segmentation clock is an auto-inhibitory negative feedback loop involving her/Hes transcriptional repressors. Although the `clock and wave front' model of somitogenesis is widely accepted, there are still many aspects of clock regulation that are not understood, and yet other aspects that may be challenged as our ability to examine oscillation dynamics in vivo becomes more sophisticated. It is only over the last few years that we have been able to watch the segmentation clock oscillate in living embryos and only very recently that have we been able to do so with single cell resolution. As our ability to detect rapid biological oscillations improves, more and more examples of biological oscillators controlling diverse cellular responses and cell fate decisions are being discovered, underscoring a critical need to understand how they are regulated. In this proposal, we will focus on characterizing the cis regulatory elements and trans-acting factors required for a largely understudied but critical aspect of oscillatory systems - that of cyclic transcript decay. Rapid transcript turnover is critical in oscillatory systems like the vertebrate segmentation clock, where every round of transcription must be followed by a wave of transcript decay to sustain oscillations. We already have one factor in hand, Pnrc2, which will greatly facilitate the identification of a cyclic transcript decay complex. We anticipate that this work ill broadly impact our understanding of regulation of RNA turnover in many developmental contexts. Rapid molecular oscillators are not only important for generating segmental pattern during development, but also for promoting heterogeneous responses in neural stem cells, and for biasing embryonic stem cells toward different cell fates. Additionally, Hes1 upregulation promotes rhabdomyosarcoma, an aggressive childhood cancer. Thus, the more we understand cyclic regulation, the more likely we are to develop promising treatments or therapeutics for human disease. We propose to uncover regulatory mechanisms, elements, and factors that control oscillation dynamics in one such oscillatory system, the vertebrate segmentation clock, and anticipate that our work will impact studies in fields as diverse as developmental biology, stem cell biology, tissue engineering, and possibly cancer cell biology.

Public Health Relevance

Rapid molecular oscillators are important for generating segmental pattern during development, for promoting heterogeneous responses in neural stem cells, and for biasing embryonic stem cells toward different cell fates. We propose to uncover regulatory elements and factors that control molecular oscillation in one such oscillatory system, the vertebrate segmentation clock, and propose that our discoveries will impact studies in fields as diverse as stem cell biology, tissue engineering, and even cancer cell biology.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM117964-03
Application #
9278200
Study Section
Special Emphasis Panel (ZRG1-CB-T (03)M)
Program Officer
Hoodbhoy, Tanya
Project Start
2015-09-18
Project End
2019-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
3
Fiscal Year
2017
Total Cost
$315,700
Indirect Cost
$110,700
Name
Ohio State University
Department
Genetics
Type
Schools of Arts and Sciences
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Morrow, Zachary T; Maxwell, Adrienne M; Hoshijima, Kazuyuki et al. (2017) tbx6l and tbx16 are redundantly required for posterior paraxial mesoderm formation during zebrafish embryogenesis. Dev Dyn 246:759-769
Berberoglu, Michael A; Gallagher, Thomas L; Morrow, Zachary T et al. (2017) Satellite-like cells contribute to pax7-dependent skeletal muscle repair in adult zebrafish. Dev Biol 424:162-180
Gallagher, Thomas L; Tietz, Kiel T; Morrow, Zachary T et al. (2017) Pnrc2 regulates 3'UTR-mediated decay of segmentation clock-associated transcripts during zebrafish segmentation. Dev Biol 429:225-239