# Elucidating the Role of Metabolism in Regulating the Vertebrate Segmentation Clock

> **NIH NIH F31** · HARVARD MEDICAL SCHOOL · 2020 · $31,164

## Abstract

Elucidating the Role of Metabolism in Regulating the Vertebrate Segmentation Clock
During vertebrate embryogenesis, segmentation is established by the sequential and rhythmic formation of
somites from paraxial mesoderm. The periodicity of somite formation is controlled by traveling waves of gene
expression collectively known as the segmentation clock. Despite considerable progress in identifying the
signaling dynamics that sustain and synchronize oscillations in the presomitic mesoderm, much less is known
about the pacemaker mechanisms that initiate and control the period of the segmentation clock. Current
models focus on splicing and nuclear export delay kinetics of individual Hes/Her cyclic genes. However, not all
oscillating genes depend on Hes/Her activity and partial segmentation is still observed in Hes/Her mutant
embryos. Thus, the identity of the clock pacemaker remains largely elusive. We hypothesize that the
segmentation clock might instead be regulated by a metabolic pacemaker. In recent years, it has become clear
that oscillatory cells in the presomitic mesoderm exhibit specialized metabolic properties, including high levels
of oxidative glycolysis reminiscent of the Warburg effect in cancer cells. A posterior to anterior gradient of
glycolytic activity is present in the presomitic mesoderm and might control the dynamics of segmentation clock
waves. Furthermore, treatment of embryos with glycolysis and oxidative respiration inhibitors specifically
blocks oscillations of the segmentation clock in posterior presomitic mesoderm cells. We propose to test the
role of metabolism in regulating the period of the segmentation clock by making use an in vitro pluripotent stem
cell-derived model of the human segmentation clock that we recently developed. We will use fluorescent
metabolic sensors to determine whether metabolic oscillations take place in human presomitic mesoderm cells
and test the effect of metabolic perturbations on the oscillatory period of these cells in vitro. We will furthermore
develop a parallel mouse system based on embryonic stem cells and use it to perform cross-species
comparisons. Given that the mouse segmentation clock operates more than two times faster than its human
counterpart, comparing these two species is likely to provide insights into period control. Using the Seahorse
technology and metabolic flux analysis, we will compare the metabolic properties of mouse and human
presomitic mesoderm cells to find parameters that scale with clock period. The proposed experiments should
inform the regulation of segmentation clock period, with important implications for the understanding of
evolutionary processes and human disease.

## Key facts

- **NIH application ID:** 9999285
- **Project number:** 5F31HD100033-02
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Margarete Diaz Cuadros
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $31,164
- **Award type:** 5
- **Project period:** 2019-09-30 → 2021-08-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999285

## Citation

> US National Institutes of Health, RePORTER application 9999285, Elucidating the Role of Metabolism in Regulating the Vertebrate Segmentation Clock (5F31HD100033-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9999285. Licensed CC0.

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